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Find video protocols related to scientific articles indexed in Pubmed.
Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.
Diabetes
PUBLISHED: 09-03-2014
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Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. Most genome-wide association loci for FPG so far been identified were derived from populations with European ancestry with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 non-diabetic subjects with East Asian ancestry. Follow-up replication analyses in up to additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1 and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.
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Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus.
PLoS Genet.
PUBLISHED: 09-01-2014
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Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3'UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.
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Defining the role of common variation in the genomic and biological architecture of adult human height.
Andrew R Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H Pers, Stefan Gustafsson, Audrey Y Chu, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L Buchkovich, Damien C Croteau-Chonka, Felix R Day, Yanan Duan, Tove Fall, Rudolf Fehrmann, Teresa Ferreira, Anne U Jackson, Juha Karjalainen, Ken Sin Lo, Adam E Locke, Reedik Mägi, Evelin Mihailov, Eleonora Porcu, Joshua C Randall, André Scherag, Anna A E Vinkhuyzen, Harm-Jan Westra, Thomas W Winkler, Tsegaselassie Workalemahu, Jing Hua Zhao, Devin Absher, Eva Albrecht, Denise Anderson, Jeffrey Baron, Marian Beekman, Ayse Demirkan, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Ross M Fraser, Anuj Goel, Jian Gong, Anne E Justice, Stavroula Kanoni, Marcus E Kleber, Kati Kristiansson, Unhee Lim, Vaneet Lotay, Julian C Lui, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Michael A Nalls, Dale R Nyholt, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Inga Prokopenko, Janina S Ried, Stephan Ripke, Dmitry Shungin, Alena Stančáková, Rona J Strawbridge, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W van der Laan, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Zhaoming Wang, Loïc Yengo, Weihua Zhang, Uzma Afzal, Johan Arnlöv, Gillian M Arscott, Stefania Bandinelli, Amy Barrett, Claire Bellis, Amanda J Bennett, Christian Berne, Matthias Blüher, Jennifer L Bolton, Yvonne Böttcher, Heather A Boyd, Marcel Bruinenberg, Brendan M Buckley, Steven Buyske, Ida H Caspersen, Peter S Chines, Robert Clarke, Simone Claudi-Boehm, Matthew Cooper, E Warwick Daw, Pim A de Jong, Joris Deelen, Graciela Delgado, Josh C Denny, Rosalie Dhonukshe-Rutten, Maria Dimitriou, Alex S F Doney, Marcus Dörr, Niina Eklund, Elodie Eury, Lasse Folkersen, Melissa E Garcia, Frank Geller, Vilmantas Giedraitis, Alan S Go, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Henrik Grönberg, Lisette C P G M de Groot, Christopher J Groves, Jeffrey Haessler, Per Hall, Toomas Haller, Göran Hallmans, Anke Hannemann, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Nancy L Heard-Costa, Quinta Helmer, Gibran Hemani, Anjali K Henders, Hans L Hillege, Mark A Hlatky, Wolfgang Hoffmann, Per Hoffmann, Oddgeir Holmen, Jeanine J Houwing-Duistermaat, Thomas Illig, Aaron Isaacs, Alan L James, Janina Jeff, Berit Johansen, Asa Johansson, Jennifer Jolley, Thorhildur Juliusdottir, Juhani Junttila, Abel N Kho, Leena Kinnunen, Norman Klopp, Thomas Kocher, Wolfgang Kratzer, Peter Lichtner, Lars Lind, Jaana Lindström, Stéphane Lobbens, Mattias Lorentzon, Yingchang Lu, Valeriya Lyssenko, Patrik K E Magnusson, Anubha Mahajan, Marc Maillard, Wendy L McArdle, Colin A McKenzie, Stela McLachlan, Paul J McLaren, Cristina Menni, Sigrun Merger, Lili Milani, Alireza Moayyeri, Keri L Monda, Mario A Morken, Gabriele Müller, Martina Müller-Nurasyid, Arthur W Musk, Narisu Narisu, Matthias Nauck, Ilja M Nolte, Markus M Nöthen, Laticia Oozageer, Stefan Pilz, Nigel W Rayner, Frida Renstrom, Neil R Robertson, Lynda M Rose, Ronan Roussel, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Fredrick R Schumacher, Heribert Schunkert, Robert A Scott, Joban Sehmi, Thomas Seufferlein, Jianxin Shi, Karri Silventoinen, Johannes H Smit, Albert Vernon Smith, Joanna Smolonska, Alice V Stanton, Kathleen Stirrups, David J Stott, Heather M Stringham, Johan Sundström, Morris A Swertz, Ann-Christine Syvänen, Bamidele O Tayo, Gudmar Thorleifsson, Jonathan P Tyrer, Suzanne van Dijk, Natasja M van Schoor, Nathalie van der Velde, Diana van Heemst, Floor V A van Oort, Sita H Vermeulen, Niek Verweij, Judith M Vonk, Lindsay L Waite, Melanie Waldenberger, Roman Wennauer, Lynne R Wilkens, Christina Willenborg, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Alan F Wright, Qunyuan Zhang, Dominique Arveiler, Stephan J L Bakker, John Beilby, Richard N Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Dorret I Boomsma, Stefan R Bornstein, Pascal Bovet, Paolo Brambilla, Morris J Brown, Harry Campbell, Mark J Caulfield, Aravinda Chakravarti, Rory Collins, Francis S Collins, Dana C Crawford, L Adrienne Cupples, John Danesh, Ulf de Faire, Hester M den Ruijter, Raimund Erbel, Jeanette Erdmann, Johan G Eriksson, Martin Farrall, Ele Ferrannini, Jean Ferrières, Ian Ford, Nita G Forouhi, Terrence Forrester, Ron T Gansevoort, Pablo V Gejman, Christian Gieger, Alain Golay, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, David W Haas, Alistair S Hall, Tamara B Harris, Andrew T Hattersley, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Lucia A Hindorff, Aroon D Hingorani, Albert Hofman, G Kees Hovingh, Steve E Humphries, Steven C Hunt, Elina Hyppönen, Kevin B Jacobs, Marjo-Riitta Järvelin, Pekka Jousilahti, Antti M Jula, Jaakko Kaprio, John J P Kastelein, Manfred Kayser, Frank Kee, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Jaspal S Kooner, Charles Kooperberg, Seppo Koskinen, Peter Kovacs, Aldi T Kraja, Meena Kumari, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Sara Lupoli, Pamela A F Madden, Satu Mannisto, Paolo Manunta, André Marette, Tara C Matise, Barbara McKnight, Thomas Meitinger, Frans L Moll, Grant W Montgomery, Andrew D Morris, Andrew P Morris, Jeffrey C Murray, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Willem H Ouwehand, Gerard Pasterkamp, Annette Peters, Peter P Pramstaller, Jackie F Price, Lu Qi, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Marylyn Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Peter E H Schwarz, Sylvain Sebert, Peter Sever, Alan R Shuldiner, Juha Sinisalo, Valgerdur Steinthorsdottir, Ronald P Stolk, Jean-Claude Tardif, Anke Tönjes, Angelo Tremblay, Elena Tremoli, Jarmo Virtamo, Marie-Claude Vohl, , Philippe Amouyel, Folkert W Asselbergs, Themistocles L Assimes, Murielle Bochud, Bernhard O Boehm, Eric Boerwinkle, Erwin P Bottinger, Claude Bouchard, Stéphane Cauchi, John C Chambers, Stephen J Chanock, Richard S Cooper, Paul I W de Bakker, George Dedoussis, Luigi Ferrucci, Paul W Franks, Philippe Froguel, Leif C Groop, Christopher A Haiman, Anders Hamsten, M Geoffrey Hayes, Jennie Hui, David J Hunter, Kristian Hveem, J Wouter Jukema, Robert C Kaplan, Mika Kivimäki, Diana Kuh, Markku Laakso, Yongmei Liu, Nicholas G Martin, Winfried März, Mads Melbye, Susanne Moebus, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin N A Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Joseph E Powell, Chris Power, Thomas Quertermous, Rainer Rauramaa, Eva Reinmaa, Paul M Ridker, Fernando Rivadeneira, Jerome I Rotter, Timo E Saaristo, Danish Saleheen, David Schlessinger, P Eline Slagboom, Harold Snieder, Tim D Spector, Konstantin Strauch, Michael Stumvoll, Jaakko Tuomilehto, Matti Uusitupa, Pim van der Harst, Henry Völzke, Mark Walker, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Pieter Zanen, Panos Deloukas, Iris M Heid, Cecilia M Lindgren, Karen L Mohlke, Elizabeth K Speliotes, Unnur Thorsteinsdottir, Inês Barroso, Caroline S Fox, Kari E North, David P Strachan, Jacques S Beckmann, Sonja I Berndt, Michael Boehnke, Ingrid B Borecki, Mark I McCarthy, Andres Metspalu, Kari Stefansson, André G Uitterlinden, Cornelia M van Duijn, Lude Franke, Cristen J Willer, Alkes L Price, Guillaume Lettre, Ruth J F Loos, Michael N Weedon, Erik Ingelsson, Jeffrey R O'Connell, Gonçalo R Abecasis, Daniel I Chasman, Michael E Goddard, Peter M Visscher, Joel N Hirschhorn, Timothy M Frayling.
Nat. Genet.
PUBLISHED: 08-29-2014
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Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ?2,000, ?3,700 and ?9,500 SNPs explained ?21%, ?24% and ?29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/?-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
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FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals.
Qibin Qi, Tuomas O Kilpeläinen, Mary K Downer, Toshiko Tanaka, Caren E Smith, Ivonne Sluijs, Emily Sonestedt, Audrey Y Chu, Frida Renstrom, Xiaochen Lin, Lars H Angquist, Jinyan Huang, Zhonghua Liu, Yanping Li, Muhammad Asif Ali, Min Xu, Tarunveer Singh Ahluwalia, Jolanda M A Boer, Peng Chen, Makoto Daimon, Johan Eriksson, Markus Perola, Yechiel Friedlander, Yu-Tang Gao, Denise H M Heppe, John W Holloway, Denise K Houston, Stavroula Kanoni, Yu-Mi Kim, Maarit A Laaksonen, Tiina Jääskeläinen, Nanette R Lee, Terho Lehtimäki, Rozenn N Lemaitre, Wei Lu, Robert N Luben, Ani Manichaikul, Satu Mannisto, Pedro Marques-Vidal, Keri L Monda, Julius S Ngwa, Louis Pérusse, Frank J A van Rooij, Yong-Bing Xiang, Wanqing Wen, Mary K Wojczynski, Jingwen Zhu, Ingrid B Borecki, Claude Bouchard, Qiuyin Cai, Cyrus Cooper, George V Dedoussis, Panos Deloukas, Luigi Ferrucci, Nita G Forouhi, Torben Hansen, Lene Christiansen, Albert Hofman, Ingegerd Johansson, Torben Jørgensen, Shigeru Karasawa, Kay-Tee Khaw, Mi-Kyung Kim, Kati Kristiansson, Huaixing Li, Xu Lin, Yongmei Liu, Kurt K Lohman, Jirong Long, Vera Mikkilä, Dariush Mozaffarian, Kari North, Oluf Pedersen, Olli Raitakari, Harri Rissanen, Jaakko Tuomilehto, Yvonne T van der Schouw, André G Uitterlinden, M Carola Zillikens, Oscar H Franco, E Shyong Tai, Xiao Ou Shu, David S Siscovick, Ulla Toft, W M Monique Verschuren, Peter Vollenweider, Nicholas J Wareham, Jacqueline C M Witteman, Wei Zheng, Paul M Ridker, Jae H Kang, Liming Liang, Majken K Jensen, Gary C Curhan, Louis R Pasquale, David J Hunter, Karen L Mohlke, Matti Uusitupa, L Adrienne Cupples, Tuomo Rankinen, Marju Orho-Melander, Tao Wang, Daniel I Chasman, Paul W Franks, Thorkild I A Sørensen, Frank B Hu, Ruth J F Loos, Jennifer A Nettleton, Lu Qi.
Hum. Mol. Genet.
PUBLISHED: 08-07-2014
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FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
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Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.
Wanqing Wen, Wei Zheng, Yukinori Okada, Fumihiko Takeuchi, Yasuharu Tabara, Joo-Yeon Hwang, Rajkumar Dorajoo, Huaixing Li, Fuu-Jen Tsai, Xiaobo Yang, Jiang He, Ying Wu, Meian He, Yi Zhang, Jun Liang, Xiuqing Guo, Wayne Huey-Herng Sheu, Ryan Delahanty, Xingyi Guo, Michiaki Kubo, Ken Yamamoto, Takayoshi Ohkubo, Min Jin Go, Jian Jun Liu, Wei Gan, Ching-Chu Chen, Yong Gao, Shengxu Li, Nanette R Lee, Chen Wu, Xueya Zhou, Huaidong Song, Jie Yao, I-Te Lee, Jirong Long, Tatsuhiko Tsunoda, Koichi Akiyama, Naoyuki Takashima, Yoon Shin Cho, Rick Th Ong, Ling Lu, Chien-Hsiun Chen, Aihua Tan, Treva K Rice, Linda S Adair, Lixuan Gui, Matthew Allison, Wen-Jane Lee, Qiuyin Cai, Minoru Isomura, Satoshi Umemura, Young Jin Kim, Mark Seielstad, James Hixson, Yong-Bing Xiang, Masato Isono, Bong-Jo Kim, Xueling Sim, Wei Lu, Toru Nabika, Juyoung Lee, Wei-Yen Lim, Yu-Tang Gao, Ryoichi Takayanagi, Dae-Hee Kang, Tien Yin Wong, Chao Agnes Hsiung, I-Chien Wu, Jyh-Ming Jimmy Juang, Jiajun Shi, Bo Youl Choi, Tin Aung, Frank Hu, Mi Kyung Kim, Wei Yen Lim, Tzung-Dao Wang, Min-Ho Shin, Jeannette Lee, Bu-Tian Ji, Young-Hoon Lee, Terri L Young, Dong Hoon Shin, Byung-Yeol Chun, Myeong-Chan Cho, Bok-Ghee Han, Chii-Min Hwu, Themistocles L Assimes, Devin Absher, Xiaofei Yan, Eric Kim, Jane Z Kuo, Soonil Kwon, Kent D Taylor, Yii-Der I Chen, Jerome I Rotter, Lu Qi, Dingliang Zhu, Tangchun Wu, Karen L Mohlke, Dongfeng Gu, Zengnan Mo, Jer-Yuarn Wu, Xu Lin, Tetsuro Miki, E Shyong Tai, Jong-Young Lee, Norihiro Kato, Xiao-Ou Shu, Toshihiro Tanaka.
Hum. Mol. Genet.
PUBLISHED: 05-26-2014
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Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ?2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.
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Multi-ethnic fine-mapping of 14 central adiposity loci.
Hum. Mol. Genet.
PUBLISHED: 04-23-2014
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The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.
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Strategies to fine-map genetic associations with lipid levels by combining epigenomic annotations and liver-specific transcription profiles.
Genomics
PUBLISHED: 03-04-2014
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Characterization of the epigenome promises to yield the functional elements buried in the human genome sequence, thus helping to annotate non-coding DNA polymorphisms with regulatory functions. Here, we develop two novel strategies to combine epigenomic data with transcriptomic profiles in humans or mice to prioritize potential candidate SNPs associated with lipid levels by genome-wide association study (GWAS). First, after confirming that lipid-associated loci that are also expression quantitative trait loci (eQTL) in human livers are enriched for ENCODE regulatory marks in the human hepatocellular HepG2 cell line, we prioritize candidate SNPs based on the number of these marks that overlap the variant position. This method recognized the known SORT1 rs12740374 regulatory SNP associated with LDL-cholesterol, and highlighted candidate functional SNPs at 15 additional lipid loci. In the second strategy, we combine ENCODE chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) data and liver expression datasets from knockout mice lacking specific transcription factors. This approach identified SNPs in specific transcription factor binding sites that are located near target genes of these transcription factors. We show that FOXA2 transcription factor binding sites are enriched at lipid-associated loci and experimentally validate that alleles of one such proxy SNP located near the FOXA2 target gene BIRC5 show allelic differences in FOXA2-DNA binding and enhancer activity. These methods can be used to generate testable hypotheses for many non-coding SNPs associated with complex diseases or traits.
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
Nat. Genet.
PUBLISHED: 02-10-2014
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Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
, Anubha Mahajan, Min Jin Go, Weihua Zhang, Jennifer E Below, Kyle J Gaulton, Teresa Ferreira, Momoko Horikoshi, Andrew D Johnson, Maggie C Y Ng, Inga Prokopenko, Danish Saleheen, Xu Wang, Eleftheria Zeggini, Gonçalo R Abecasis, Linda S Adair, Peter Almgren, Mustafa Atalay, Tin Aung, Damiano Baldassarre, Beverley Balkau, Yuqian Bao, Anthony H Barnett, Inês Barroso, Abdul Basit, Latonya F Been, John Beilby, Graeme I Bell, Rafn Benediktsson, Richard N Bergman, Bernhard O Boehm, Eric Boerwinkle, Lori L Bonnycastle, Noel Burtt, Qiuyin Cai, Harry Campbell, Jason Carey, Stéphane Cauchi, Mark Caulfield, Juliana C N Chan, Li-Ching Chang, Tien-Jyun Chang, Yi-Cheng Chang, Guillaume Charpentier, Chien-Hsiun Chen, Han Chen, Yuan-Tsong Chen, Kee-Seng Chia, Manickam Chidambaram, Peter S Chines, Nam H Cho, Young Min Cho, Lee-Ming Chuang, Francis S Collins, Marylin C Cornelis, David J Couper, Andrew T Crenshaw, Rob M Van Dam, John Danesh, Debashish Das, Ulf de Faire, George Dedoussis, Panos Deloukas, Antigone S Dimas, Christian Dina, Alex S Doney, Peter J Donnelly, Mozhgan Dorkhan, Cornelia van Duijn, Josée Dupuis, Sarah Edkins, Paul Elliott, Valur Emilsson, Raimund Erbel, Johan G Eriksson, Jorge Escobedo, Tonu Esko, Elodie Eury, Jose C Florez, Pierre Fontanillas, Nita G Forouhi, Tom Forsén, Caroline Fox, Ross M Fraser, Timothy M Frayling, Philippe Froguel, Philippe Frossard, Yutang Gao, Karl Gertow, Christian Gieger, Bruna Gigante, Harald Grallert, George B Grant, Leif C Grrop, Chrisropher J Groves, Elin Grundberg, Candace Guiducci, Anders Hamsten, Bok-Ghee Han, Kazuo Hara, Neelam Hassanali, Andrew T Hattersley, Caroline Hayward, Asa K Hedman, Christian Herder, Albert Hofman, Oddgeir L Holmen, Kees Hovingh, Astradur B Hreidarsson, Cheng Hu, Frank B Hu, Jennie Hui, Steve E Humphries, Sarah E Hunt, David J Hunter, Kristian Hveem, Zafar I Hydrie, Hiroshi Ikegami, Thomas Illig, Erik Ingelsson, Muhammed Islam, Bo Isomaa, Anne U Jackson, Tazeen Jafar, Alan James, Weiping Jia, Karl-Heinz Jöckel, Anna Jonsson, Jeremy B M Jowett, Takashi Kadowaki, Hyun Min Kang, Stavroula Kanoni, Wen Hong L Kao, Sekar Kathiresan, Norihiro Kato, Prasad Katulanda, Kirkka M Keinanen-Kiukaanniemi, Ann M Kelly, Hassan Khan, Kay-Tee Khaw, Chiea-Chuen Khor, Hyung-Lae Kim, Sangsoo Kim, Young Jin Kim, Leena Kinnunen, Norman Klopp, Augustine Kong, Eeva Korpi-Hyövälti, Sudhir Kowlessur, Peter Kraft, Jasmina Kravic, Malene M Kristensen, S Krithika, Ashish Kumar, Jesus Kumate, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Vasiliki Lagou, Timo A Lakka, Claudia Langenberg, Cordelia Langford, Robert Lawrence, Karin Leander, Jen-Mai Lee, Nanette R Lee, Man Li, Xinzhong Li, Yun Li, Junbin Liang, Samuel Liju, Wei-Yen Lim, Lars Lind, Cecilia M Lindgren, Eero Lindholm, Ching-Ti Liu, Jian Jun Liu, Stéphane Lobbens, Jirong Long, Ruth J F Loos, Wei Lu, Jian'an Luan, Valeriya Lyssenko, Ronald C W Ma, Shiro Maeda, Reedik Mägi, Satu Mannisto, David R Matthews, James B Meigs, Olle Melander, Andres Metspalu, Julia Meyer, Ghazala Mirza, Evelin Mihailov, Susanne Moebus, Viswanathan Mohan, Karen L Mohlke, Andrew D Morris, Thomas W Mühleisen, Martina Müller-Nurasyid, Bill Musk, Jiro Nakamura, Eitaro Nakashima, Pau Navarro, Peng-Keat Ng, Alexandra C Nica, Peter M Nilsson, Inger Njølstad, Markus M Nöthen, Keizo Ohnaka, Twee Hee Ong, Katharine R Owen, Colin N A Palmer, James S Pankow, Kyong Soo Park, Melissa Parkin, Sonali Pechlivanis, Nancy L Pedersen, Leena Peltonen, John R B Perry, Annette Peters, Janini M Pinidiyapathirage, Carl G Platou, Simon Potter, Jackie F Price, Lu Qi, Venkatesan Radha, Loukianos Rallidis, Asif Rasheed, Wolfgang Rathman, Rainer Rauramaa, Soumya Raychaudhuri, N William Rayner, Simon D Rees, Emil Rehnberg, Samuli Ripatti, Neil Robertson, Michael Roden, Elizabeth J Rossin, Igor Rudan, Denis Rybin, Timo E Saaristo, Veikko Salomaa, Juha Saltevo, Maria Samuel, Dharambir K Sanghera, Jouko Saramies, James Scott, Laura J Scott, Robert A Scott, Ayellet V Segrè, Joban Sehmi, Bengt Sennblad, Nabi Shah, Sonia Shah, A Samad Shera, Xiao Ou Shu, Alan R Shuldiner, Gunnar Sigurđsson, Eric Sijbrands, Angela Silveira, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S Small, Wing Yee So, Alena Stančáková, Kari Stefansson, Gerald Steinbach, Valgerdur Steinthorsdottir, Kathleen Stirrups, Rona J Strawbridge, Heather M Stringham, Qi Sun, Chen Suo, Ann-Christine Syvänen, Ryoichi Takayanagi, Fumihiko Takeuchi, Wan Ting Tay, Tanya M Teslovich, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Emmi Tikkanen, Joseph Trakalo, Elena Tremoli, Mieke D Trip, Fuu Jen Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, André G Uitterlinden, Adán Valladares-Salgado, Sailaja Vedantam, Fabrizio Veglia, Benjamin F Voight, Congrong Wang, Nicholas J Wareham, Roman Wennauer, Ananda R Wickremasinghe, Tom Wilsgaard, James F Wilson, Steven Wiltshire, Wendy Winckler, Tien Yin Wong, Andrew R Wood, Jer-Yuarn Wu, Ying Wu, Ken Yamamoto, Toshimasa Yamauchi, Mingyu Yang, Loïc Yengo, Mitsuhiro Yokota, Robin Young, Delilah Zabaneh, Fan Zhang, Rong Zhang, Wei Zheng, Paul Z Zimmet, David Altshuler, Donald W Bowden, Yoon Shin Cho, Nancy J Cox, Miguel Cruz, Craig L Hanis, Jaspal Kooner, Jong-Young Lee, Mark Seielstad, Yik Ying Teo, Michael Boehnke, Esteban J Parra, Jonh C Chambers, E Shyong Tai, Mark I McCarthy, Andrew P Morris.
Nat. Genet.
PUBLISHED: 01-17-2014
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To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
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A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell.
Am. J. Hum. Genet.
PUBLISHED: 01-16-2014
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Genome-wide association studies (GWASs) have identified more than 70 loci associated with type 2 diabetes (T2D), but for most, the underlying causal variants, associated genes, and functional mechanisms remain unknown. At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identified a functional regulatory DNA variant, a candidate target gene, and a plausible underlying molecular mechanism. Fine mapping, conditional analyses, and exome array genotyping in 8,635 individuals from the Metabolic Syndrome in Men study confirmed a single major association signal between fasting proinsulin and noncoding variants (p = 7.4 × 10(-50)). Measurement of allele-specific mRNA levels in human pancreatic islet samples heterozygous for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with increased ARAP1 expression (p < 0.02). We evaluated four candidate functional SNPs for allelic effects on transcriptional activity by performing reporter assays in rodent pancreatic beta cell lines. The C allele of rs11603334, located near one of the ARAP1 promoters, exhibited 2-fold higher transcriptional activity than did the T allele (p < 0.0001); three other candidate SNPs showed no allelic differences. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele. Collectively, these data suggest that the T2D-risk allele of rs11603334 could abrogate binding of a complex containing PAX6 and PAX4 and thus lead to increased promoter activity and ARAP1 expression in human pancreatic islets. This work suggests that increased ARAP1 expression might contribute to T2D susceptibility at this GWAS locus.
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Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis.
Clin. Endocrinol. (Oxf)
PUBLISHED: 01-12-2014
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Genome-wide association studies have identified many obesity/body mass index (BMI)-associated loci in Europeans and East Asians. Since then, a large number of studies have investigated the role of BMI-associated loci in the development of type 2 diabetes (T2D). However, the results have been inconsistent. The objective of this study was to investigate the associations of eleven obesity/BMI loci with T2D risk and explore how BMI influences this risk.
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Association studies with imputed variants using expectation-maximization likelihood-ratio tests.
PLoS ONE
PUBLISHED: 01-01-2014
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Genotype imputation has become standard practice in modern genetic studies. As sequencing-based reference panels continue to grow, increasingly more markers are being well or better imputed but at the same time, even more markers with relatively low minor allele frequency are being imputed with low imputation quality. Here, we propose new methods that incorporate imputation uncertainty for downstream association analysis, with improved power and/or computational efficiency. We consider two scenarios: I) when posterior probabilities of all potential genotypes are estimated; and II) when only the one-dimensional summary statistic, imputed dosage, is available. For scenario I, we have developed an expectation-maximization likelihood-ratio test for association based on posterior probabilities. When only imputed dosages are available (scenario II), we first sample the genotype probabilities from its posterior distribution given the dosages, and then apply the EM-LRT on the sampled probabilities. Our simulations show that type I error of the proposed EM-LRT methods under both scenarios are protected. Compared with existing methods, EM-LRT-Prob (for scenario I) offers optimal statistical power across a wide spectrum of MAF and imputation quality. EM-LRT-Dose (for scenario II) achieves a similar level of statistical power as EM-LRT-Prob and, outperforms the standard Dosage method, especially for markers with relatively low MAF or imputation quality. Applications to two real data sets, the Cebu Longitudinal Health and Nutrition Survey study and the Women's Health Initiative Study, provide further support to the validity and efficiency of our proposed methods.
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
Diabetes
PUBLISHED: 12-02-2013
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Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2.
Hum. Mol. Genet.
PUBLISHED: 10-08-2013
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Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
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Discovery and refinement of loci associated with lipid levels.
, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Ron Do, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Sekar Kathiresan, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis.
Nat. Genet.
PUBLISHED: 09-13-2013
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Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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Genetic association with lipids in Filipinos: waist circumference modifies an APOA5 effect on triglyceride levels.
J. Lipid Res.
PUBLISHED: 09-10-2013
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Blood levels of lipoprotein cholesterol and triglycerides (TGs) are highly heritable and are major risk factors for cardiovascular disease (CVD). Approximately 100 lipid-associated loci have been identified in populations of European ancestry. We performed a genome-wide association study of lipid traits in 1,782 Filipino women from the Cebu Longitudinal Health and Nutrition Survey, and tested for evidence of interactions with waist circumference. We conducted additional association and interaction analyses in 1,719 of their young adult offspring. Genome-wide significant associations (P < 5 × 10??) were detected at APOE for low density lipoprotein cholesterol and total cholesterol, and at APOA5 for TGs. Suggestive associations (P < 10??) were detected at GCKR for TGs, and at CETP and TOM1 for high density lipoprotein cholesterol. Our data also supported the existence of allelic heterogeneity at APOA5, CETP, LIPC, and APOE. The secondary signal (Gly185Cys) at APOA5 exhibited a single nucleotide polymorphism (SNP)-by-waist circumference interaction affecting TGs (Pinteraction = 1.6 × 10??), manifested by stronger SNP effects as waist circumference increased. These findings provide the first evidence that central obesity may accentuate the effect of the TG-increasing allele of the APOA5 signal, emphasizing that CVD risk could be reduced by central obesity control.
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Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure loci.
Hypertension
PUBLISHED: 09-03-2013
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We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage 1) followed by replication study of up to 28,783 participants (stage 2). For novel loci, statistical significance was determined by a P<5.0×10(-8) in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10(-3). No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 (P=7.5×10(-15)), rs2681492 at ATP2B1 (P=3.4×10(-7)), rs11191593 at NT5C2 (1.1×10(-6)), rs3824755 at CYP17A1 (P=1.2×10(-6)), and rs13149993 at FGF5 (P=2.4×10(-4)). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10(-5)) and rs11191593 at NT5C2 (P=1.1×10(-3)), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10(-3)) and rs2681492 at ATP2B1 (P=9.0×10(-3)). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm?Hg for mean arterial pressure and from 0.03 to 0.21 mm?Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.
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Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
Diabetes
PUBLISHED: 07-08-2013
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Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
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Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.
PLoS Genet.
PUBLISHED: 07-01-2013
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Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction ?=?0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n?=?39,810, Pinteraction ?=?0.014 vs. n?=?71,611, Pinteraction ?=?0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction ?=?0.003) and the SEC16B rs10913469 (Pinteraction ?=?0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
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Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
Joshua C Randall, Thomas W Winkler, Zoltan Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tonu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, André Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, , Amélie Bonnefond, Philippe Froguel, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Järvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimäki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, Iris M Heid.
PLoS Genet.
PUBLISHED: 06-01-2013
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Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
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Association of ketone body levels with hyperglycemia and type 2 diabetes in 9,398 Finnish men.
Diabetes
PUBLISHED: 04-04-2013
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We investigated the association of the levels of ketone bodies (KBs) with hyperglycemia and with 62 genetic risk variants regulating glucose levels or type 2 diabetes in the population-based Metabolic Syndrome in Men (METSIM) study, including 9,398 Finnish men without diabetes or newly diagnosed type 2 diabetes. Increasing fasting and 2-h plasma glucose levels were associated with elevated levels of acetoacetate (AcAc) and ?-hydroxybutyrate (BHB). AcAc and BHB predicted an increase in the glucose area under the curve in an oral glucose tolerance test, and AcAc predicted the conversion to type 2 diabetes in a 5-year follow-up of the METSIM cohort. Impaired insulin secretion, but not insulin resistance, explained these findings. Of the 62 single nucleotide polymorphisms associated with the risk of type 2 diabetes or hyperglycemia, the glucose-increasing C allele of GCKR significantly associated with elevated levels of fasting BHB levels. Adipose tissue mRNA expression levels of genes involved in ketolysis were significantly associated with insulin sensitivity (Matsuda index). In conclusion, high levels of KBs predicted subsequent worsening of hyperglycemia, and a common variant of GCKR was significantly associated with BHB levels.
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Sonja I Berndt, Stefan Gustafsson, Reedik Mägi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, Tonu Esko, Tove Fall, Teresa Ferreira, Davide Gentilini, Anne U Jackson, Jian'an Luan, Joshua C Randall, Sailaja Vedantam, Cristen J Willer, Thomas W Winkler, Andrew R Wood, Tsegaselassie Workalemahu, Yi-Juan Hu, Sang Hong Lee, Liming Liang, Dan-Yu Lin, Josine L Min, Benjamin M Neale, Gudmar Thorleifsson, Jian Yang, Eva Albrecht, Najaf Amin, Jennifer L Bragg-Gresham, Gemma Cadby, Martin den Heijer, Niina Eklund, Krista Fischer, Anuj Goel, Jouke-Jan Hottenga, Jennifer E Huffman, Ivonne Jarick, Asa Johansson, Toby Johnson, Stavroula Kanoni, Marcus E Kleber, Inke R König, Kati Kristiansson, Zoltan Kutalik, Claudia Lamina, Cécile Lecoeur, Guo Li, Massimo Mangino, Wendy L McArdle, Carolina Medina-Gomez, Martina Müller-Nurasyid, Julius S Ngwa, Ilja M Nolte, Lavinia Paternoster, Sonali Pechlivanis, Markus Perola, Marjolein J Peters, Michael Preuss, Lynda M Rose, Jianxin Shi, Dmitry Shungin, Albert Vernon Smith, Rona J Strawbridge, Ida Surakka, Alexander Teumer, Mieke D Trip, Jonathan Tyrer, Jana V van Vliet-Ostaptchouk, Liesbeth Vandenput, Lindsay L Waite, Jing Hua Zhao, Devin Absher, Folkert W Asselbergs, Mustafa Atalay, Antony P Attwood, Anthony J Balmforth, Hanneke Basart, John Beilby, Lori L Bonnycastle, Paolo Brambilla, Marcel Bruinenberg, Harry Campbell, Daniel I Chasman, Peter S Chines, Francis S Collins, John M Connell, William O Cookson, Ulf de Faire, Femmie de Vegt, Mariano Dei, Maria Dimitriou, Sarah Edkins, Karol Estrada, David M Evans, Martin Farrall, Marco M Ferrario, Jean Ferrières, Lude Franke, Francesca Frau, Pablo V Gejman, Harald Grallert, Henrik Grönberg, Vilmundur Gudnason, Alistair S Hall, Per Hall, Anna-Liisa Hartikainen, Caroline Hayward, Nancy L Heard-Costa, Andrew C Heath, Johannes Hebebrand, Georg Homuth, Frank B Hu, Sarah E Hunt, Elina Hyppönen, Carlos Iribarren, Kevin B Jacobs, John-Olov Jansson, Antti Jula, Mika Kähönen, Sekar Kathiresan, Frank Kee, Kay-Tee Khaw, Mika Kivimäki, Wolfgang Koenig, Aldi T Kraja, Meena Kumari, Kari Kuulasmaa, Johanna Kuusisto, Jaana H Laitinen, Timo A Lakka, Claudia Langenberg, Lenore J Launer, Lars Lind, Jaana Lindström, Jianjun Liu, Antonio Liuzzi, Marja-Liisa Lokki, Mattias Lorentzon, Pamela A Madden, Patrik K Magnusson, Paolo Manunta, Diana Marek, Winfried März, Irene Mateo Leach, Barbara McKnight, Sarah E Medland, Evelin Mihailov, Lili Milani, Grant W Montgomery, Vincent Mooser, Thomas W Mühleisen, Patricia B Munroe, Arthur W Musk, Narisu Narisu, Gerjan Navis, George Nicholson, Ellen A Nohr, Ken K Ong, Ben A Oostra, Colin N A Palmer, Aarno Palotie, John F Peden, Nancy Pedersen, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Inga Prokopenko, Carolin Pütter, Aparna Radhakrishnan, Olli Raitakari, Augusto Rendon, Fernando Rivadeneira, Igor Rudan, Timo E Saaristo, Jennifer G Sambrook, Alan R Sanders, Serena Sanna, Jouko Saramies, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, So-Youn Shin, Stefano Signorini, Juha Sinisalo, Boris Skrobek, Nicole Soranzo, Alena Stančáková, Klaus Stark, Jonathan C Stephens, Kathleen Stirrups, Ronald P Stolk, Michael Stumvoll, Amy J Swift, Eirini V Theodoraki, Barbara Thorand, David-Alexandre Trégouët, Elena Tremoli, Melanie M van der Klauw, Joyce B J van Meurs, Sita H Vermeulen, Jorma Viikari, Jarmo Virtamo, Veronique Vitart, Gérard Waeber, Zhaoming Wang, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Bernhard R Winkelmann, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Andrew Wong, Alan F Wright, M Carola Zillikens, Philippe Amouyel, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, L Adrienne Cupples, Daniele Cusi, George V Dedoussis, Jeanette Erdmann, Johan G Eriksson, Paul W Franks, Philippe Froguel, Christian Gieger, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Anke Hinney, Albert Hofman, Kees G Hovingh, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Diana Kuh, Markku Laakso, Terho Lehtimäki, Douglas F Levinson, Nicholas G Martin, Andres Metspalu, Andrew D Morris, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Willem H Ouwehand, Lyle J Palmer, Brenda Penninx, Chris Power, Michael A Province, Bruce M Psaty, Lu Qi, Rainer Rauramaa, Paul M Ridker, Samuli Ripatti, Veikko Salomaa, Nilesh J Samani, Harold Snieder, Thorkild I A Sørensen, Timothy D Spector, Kari Stefansson, Anke Tönjes, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, Pim van der Harst, Peter Vollenweider, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Gonçalo R Abecasis, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunian, Iris M Heid, David Hunter, Robert C Kaplan, Fredrik Karpe, Miriam F Moffatt, Karen L Mohlke, Jeffrey R O'Connell, Yudi Pawitan, Eric E Schadt, David Schlessinger, Valgerdur Steinthorsdottir, David P Strachan, Unnur Thorsteinsdottir, Cornelia M van Duijn, Peter M Visscher, Anna Maria Di Blasio, Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, André Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson.
Nat. Genet.
PUBLISHED: 03-14-2013
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Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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Common variants associated with plasma triglycerides and risk for coronary artery disease.
Ron Do, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Chi Gao, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, David Altshuler, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis, Mark J Daly, Benjamin M Neale, Sekar Kathiresan.
Nat. Genet.
PUBLISHED: 02-20-2013
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Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphisms effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
PLoS Genet.
PUBLISHED: 01-19-2013
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Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
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Allele-specific transcriptional activity at type 2 diabetes-associated single nucleotide polymorphisms in regions of pancreatic islet open chromatin at the JAZF1 locus.
Diabetes
PUBLISHED: 01-17-2013
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Translation of noncoding common variant association signals into meaningful molecular and biological mechanisms explaining disease susceptibility remains challenging. For the type 2 diabetes association signal in JAZF1 intron 1, we hypothesized that the underlying risk variants have cis-regulatory effects in islets or other type 2 diabetes-relevant cell types. We used maps of experimentally predicted open chromatin regions to prioritize variants for functional follow-up studies of transcriptional activity. Twelve regions containing type 2 diabetes-associated variants were tested for enhancer activity in 832/13 and MIN6 insulinoma cells. Three regions exhibited enhancer activity and only rs1635852 displayed allelic differences in enhancer activity; the type 2 diabetes risk allele T showed lower transcriptional activity than the nonrisk allele C. This risk allele showed increased binding to protein complexes, suggesting that it functions as part of a transcriptional repressor complex. We applied DNA affinity capture to identify factors in the complex and determined that the risk allele preferentially binds the pancreatic master regulator PDX1. These data suggest that the rs1635852 region in JAZF1 intron 1 is part of a cis-regulatory complex and that maps of open chromatin are useful to guide identification of variants with allelic differences in regulatory activity at type 2 diabetes loci.
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A comprehensive SNP and indel imputability database.
Bioinformatics
PUBLISHED: 01-03-2013
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Genotype imputation has become an indispensible step in genome-wide association studies (GWAS). Imputation accuracy, directly influencing downstream analysis, has shown to be improved using re-sequencing-based reference panels; however, this comes at the cost of high computational burden due to the huge number of potentially imputable markers (tens of millions) discovered through sequencing a large number of individuals. Therefore, there is an increasing need for access to imputation quality information without actually conducting imputation. To facilitate this process, we have established a publicly available SNP and indel imputability database, aiming to provide direct access to imputation accuracy information for markers identified by the 1000 Genomes Project across four major populations and covering multiple GWAS genotyping platforms.
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Population-specific coding variant underlies genome-wide association with adiponectin level.
Hum. Mol. Genet.
PUBLISHED: 10-18-2011
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Adiponectin is a protein hormone that can affect major metabolic processes including glucose regulation and fat metabolism. Our previous genome-wide association (GWA) study of circulating plasma adiponectin levels in Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) detected a 100 kb two-SNP haplotype at KNG1-ADIPOQ associated with reduced adiponectin (frequency = 0.050, P = 1.8 × 10(-25)). Subsequent genotyping of CLHNS young adult offspring detected an uncommon variant [minor allele frequency (MAF) = 0.025] located ~800 kb from ADIPOQ that showed strong association with lower adiponectin levels (P = 2.7 × 10(-15), n = 1695) and tagged a subset of KNG1-ADIPOQ haplotype carriers with even lower adiponectin levels. Sequencing of the ADIPOQ-coding region detected variant R221S (MAF = 0.015, P = 2.9 × 10(-69)), which explained 17.1% of the variance in adiponectin levels and largely accounted for the initial GWA signal in Filipinos. R221S was not present in 12 514 Europeans with previously sequenced exons. To explore the mechanism of this substitution, we re-measured adiponectin level in 20 R221S offspring carriers and 20 non-carriers using two alternative antibodies and determined that the presence of R221S resulted in artificially low quantification of adiponectin level using the original immunoassay. These data provide an example of an uncommon variant responsible for a GWA signal and demonstrate that genetic associations with phenotypes measured by antibody-based quantification methods can be affected by uncommon coding SNPs residing in the antibody target region.
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Single-nucleotide polymorphisms at five loci are associated with C-reactive protein levels in a cohort of Filipino young adults.
J. Hum. Genet.
PUBLISHED: 09-22-2011
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C-reactive protein (CRP) is a component of nonspecific immune defense and is a reliable marker of low-grade inflammation involved in obesity, type 2 diabetes and cardiovascular disease. Genome-wide association studies in middle-aged and elderly populations, predominantly of European descent, demonstrated associations of CRP levels with single-nucleotide polymorphisms (SNPs) at several loci. To examine whether the variants identified are replicated in Filipino young adults, we applied Tobit regression models to study the association of plasma CRP with 12 SNPs at seven loci in a cohort of 1691 Filipino young adults (aged 21.5±0.3 years) from the Cebu Longitudinal Health and Nutrition Survey. SNPs in or near CRP (P=3.2 × 10(-11)), HNF1A, IL6R, APOE-APOC1 and LEPR showed significant associations (P<0.05) and together explained 4.8% of the total variation in CRP. Modest interactions were observed between LEPR-rs1892534 and waist circumference (uncorrected P(interaction)=0.020) and between APOE-rs769449 and pathogen exposure (uncorrected P(interaction)=0.0073) in models predicting CRP. Our results demonstrated that variants in several loci are significantly associated with plasma CRP in Filipino young adults, suggesting shared genetic influences on circulating CRP across populations and age groups.
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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
, Georg B Ehret, Patricia B Munroe, Kenneth M Rice, Murielle Bochud, Andrew D Johnson, Daniel I Chasman, Albert V Smith, Martin D Tobin, Germaine C Verwoert, Shih-Jen Hwang, Vasyl Pihur, Peter Vollenweider, Paul F O'Reilly, Najaf Amin, Jennifer L Bragg-Gresham, Alexander Teumer, Nicole L Glazer, Lenore Launer, Jing Hua Zhao, Yurii Aulchenko, Simon Heath, Siim Sõber, Afshin Parsa, Jian'an Luan, Pankaj Arora, Abbas Dehghan, Feng Zhang, Gavin Lucas, Andrew A Hicks, Anne U Jackson, John F Peden, Toshiko Tanaka, Sarah H Wild, Igor Rudan, Wilmar Igl, Yuri Milaneschi, Alex N Parker, Cristiano Fava, John C Chambers, Ervin R Fox, Meena Kumari, Min Jin Go, Pim van der Harst, Wen Hong Linda Kao, Marketa Sjögren, D G Vinay, Myriam Alexander, Yasuharu Tabara, Sue Shaw-Hawkins, Peter H Whincup, Yongmei Liu, Gang Shi, Johanna Kuusisto, Bamidele Tayo, Mark Seielstad, Xueling Sim, Khanh-Dung Hoang Nguyen, Terho Lehtimäki, Giuseppe Matullo, Ying Wu, Tom R Gaunt, N Charlotte Onland-Moret, Matthew N Cooper, Carl G P Platou, Elin Org, Rebecca Hardy, Santosh Dahgam, Jutta Palmen, Veronique Vitart, Peter S Braund, Tatiana Kuznetsova, Cuno S P M Uiterwaal, Adebowale Adeyemo, Walter Palmas, Harry Campbell, Barbara Ludwig, Maciej Tomaszewski, Ioanna Tzoulaki, Nicholette D Palmer, Thor Aspelund, Melissa Garcia, Yen-Pei C Chang, Jeffrey R O'Connell, Nanette I Steinle, Diederick E Grobbee, Dan E Arking, Sharon L Kardia, Alanna C Morrison, Dena Hernandez, Samer Najjar, Wendy L McArdle, David Hadley, Morris J Brown, John M Connell, Aroon D Hingorani, Ian N M Day, Debbie A Lawlor, John P Beilby, Robert W Lawrence, Robert Clarke, Jemma C Hopewell, Halit Ongen, Albert W Dreisbach, Yali Li, J Hunter Young, Joshua C Bis, Mika Kähönen, Jorma Viikari, Linda S Adair, Nanette R Lee, Ming-Huei Chen, Matthias Olden, Cristian Pattaro, Judith A Hoffman Bolton, Anna Köttgen, Sven Bergmann, Vincent Mooser, Nish Chaturvedi, Timothy M Frayling, Muhammad Islam, Tazeen H Jafar, Jeanette Erdmann, Smita R Kulkarni, Stefan R Bornstein, Jürgen Gräßler, Leif Groop, Benjamin F Voight, Johannes Kettunen, Philip Howard, Andrew Taylor, Simonetta Guarrera, Fulvio Ricceri, Valur Emilsson, Andrew Plump, Inês Barroso, Kay-Tee Khaw, Alan B Weder, Steven C Hunt, Yan V Sun, Richard N Bergman, Francis S Collins, Lori L Bonnycastle, Laura J Scott, Heather M Stringham, Leena Peltonen, Markus Perola, Erkki Vartiainen, Stefan-Martin Brand, Jan A Staessen, Thomas J Wang, Paul R Burton, María Soler Artigas, Yanbin Dong, Harold Snieder, Xiaoling Wang, Haidong Zhu, Kurt K Lohman, Megan E Rudock, Susan R Heckbert, Nicholas L Smith, Kerri L Wiggins, Ayo Doumatey, Daniel Shriner, Gudrun Veldre, Margus Viigimaa, Sanjay Kinra, Dorairaj Prabhakaran, Vikal Tripathy, Carl D Langefeld, Annika Rosengren, Dag S Thelle, Anna Maria Corsi, Andrew Singleton, Terrence Forrester, Gina Hilton, Colin A McKenzie, Tunde Salako, Naoharu Iwai, Yoshikuni Kita, Toshio Ogihara, Takayoshi Ohkubo, Tomonori Okamura, Hirotsugu Ueshima, Satoshi Umemura, Susana Eyheramendy, Thomas Meitinger, H-Erich Wichmann, Yoon Shin Cho, Hyung-Lae Kim, Jong-Young Lee, James Scott, Joban S Sehmi, Weihua Zhang, Bo Hedblad, Peter Nilsson, George Davey Smith, Andrew Wong, Narisu Narisu, Alena Stančáková, Leslie J Raffel, Jie Yao, Sekar Kathiresan, Christopher J O'Donnell, Stephen M Schwartz, M Arfan Ikram, W T Longstreth, Thomas H Mosley, Sudha Seshadri, Nick R G Shrine, Louise V Wain, Mario A Morken, Amy J Swift, Jaana Laitinen, Inga Prokopenko, Paavo Zitting, Jackie A Cooper, Steve E Humphries, John Danesh, Asif Rasheed, Anuj Goel, Anders Hamsten, Hugh Watkins, Stephan J L Bakker, Wiek H van Gilst, Charles S Janipalli, K Radha Mani, Chittaranjan S Yajnik, Albert Hofman, Francesco U S Mattace-Raso, Ben A Oostra, Ayse Demirkan, Aaron Isaacs, Fernando Rivadeneira, Edward G Lakatta, Marco Orrù, Angelo Scuteri, Mika Ala-Korpela, Antti J Kangas, Leo-Pekka Lyytikäinen, Pasi Soininen, Taru Tukiainen, Peter Würtz, Rick Twee-Hee Ong, Marcus Dörr, Heyo K Kroemer, Uwe Völker, Henry Völzke, Pilar Galán, Serge Hercberg, Mark Lathrop, Diana Zelenika, Panos Deloukas, Massimo Mangino, Tim D Spector, Guangju Zhai, James F Meschia, Michael A Nalls, Pankaj Sharma, Janos Terzic, M V Kranthi Kumar, Matthew Denniff, Ewa Zukowska-Szczechowska, Lynne E Wagenknecht, F Gerald R Fowkes, Fadi J Charchar, Peter E H Schwarz, Caroline Hayward, Xiuqing Guo, Charles Rotimi, Michiel L Bots, Eva Brand, Nilesh J Samani, Ozren Polašek, Philippa J Talmud, Fredrik Nyberg, Diana Kuh, Maris Laan, Kristian Hveem, Lyle J Palmer, Yvonne T van der Schouw, Juan P Casas, Karen L Mohlke, Paolo Vineis, Olli Raitakari, Santhi K Ganesh, Tien Y Wong, E Shyong Tai, Richard S Cooper, Markku Laakso, Dabeeru C Rao, Tamara B Harris, Richard W Morris, Anna F Dominiczak, Mika Kivimäki, Michael G Marmot, Tetsuro Miki, Danish Saleheen, Giriraj R Chandak, Josef Coresh, Gerjan Navis, Veikko Salomaa, Bok-Ghee Han, Xiaofeng Zhu, Jaspal S Kooner, Olle Melander, Paul M Ridker, Stefania Bandinelli, Ulf B Gyllensten, Alan F Wright, James F Wilson, Luigi Ferrucci, Martin Farrall, Jaakko Tuomilehto, Peter P Pramstaller, Roberto Elosua, Nicole Soranzo, Eric J G Sijbrands, David Altshuler, Ruth J F Loos, Alan R Shuldiner, Christian Gieger, Pierre Meneton, André G Uitterlinden, Nicholas J Wareham, Vilmundur Gudnason, Jerome I Rotter, Rainer Rettig, Manuela Uda, David P Strachan, Jacqueline C M Witteman, Anna-Liisa Hartikainen, Jacques S Beckmann, Eric Boerwinkle, Ramachandran S Vasan, Michael Boehnke, Martin G Larson, Marjo-Riitta Järvelin, Bruce M Psaty, Gonçalo R Abecasis, Aravinda Chakravarti, Paul Elliott, Cornelia M van Duijn, Christopher Newton-Cheh, Daniel Levy, Mark J Caulfield, Toby Johnson.
Nature
PUBLISHED: 07-28-2011
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Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (?140?mm?Hg systolic blood pressure or? ?90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
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Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
Tuomas O Kilpeläinen, Lu Qi, Soren Brage, Stephen J Sharp, Emily Sonestedt, Ellen Demerath, Tariq Ahmad, Samia Mora, Marika Kaakinen, Camilla Helene Sandholt, Christina Holzapfel, Christine S Autenrieth, Elina Hyppönen, Stéphane Cauchi, Meian He, Zoltan Kutalik, Meena Kumari, Alena Stančáková, Karina Meidtner, Beverley Balkau, Jonathan T Tan, Massimo Mangino, Nicholas J Timpson, Yiqing Song, M Carola Zillikens, Kathleen A Jablonski, Melissa E Garcia, Stefan Johansson, Jennifer L Bragg-Gresham, Ying Wu, Jana V van Vliet-Ostaptchouk, N Charlotte Onland-Moret, Esther Zimmermann, Natalia V Rivera, Toshiko Tanaka, Heather M Stringham, Günther Silbernagel, Stavroula Kanoni, Mary F Feitosa, Soren Snitker, Jonatan R Ruiz, Jeffery Metter, Maria Teresa Martinez Larrad, Mustafa Atalay, Maarit Hakanen, Najaf Amin, Christine Cavalcanti-Proença, Anders Grøntved, Göran Hallmans, John-Olov Jansson, Johanna Kuusisto, Mika Kähönen, Pamela L Lutsey, John J Nolan, Luigi Palla, Oluf Pedersen, Louis Pérusse, Frida Renstrom, Robert A Scott, Dmitry Shungin, Ulla Sovio, Tuija H Tammelin, Tapani Rönnemaa, Timo A Lakka, Matti Uusitupa, Manuel Serrano Rios, Luigi Ferrucci, Claude Bouchard, Aline Meirhaeghe, Mao Fu, Mark Walker, Ingrid B Borecki, George V Dedoussis, Andreas Fritsche, Claes Ohlsson, Michael Boehnke, Stefania Bandinelli, Cornelia M van Duijn, Shah Ebrahim, Debbie A Lawlor, Vilmundur Gudnason, Tamara B Harris, Thorkild I A Sørensen, Karen L Mohlke, Albert Hofman, André G Uitterlinden, Jaakko Tuomilehto, Terho Lehtimäki, Olli Raitakari, Bo Isomaa, Pål R Njølstad, Jose C Florez, Simin Liu, Andy Ness, Timothy D Spector, E Shyong Tai, Philippe Froguel, Heiner Boeing, Markku Laakso, Michael Marmot, Sven Bergmann, Chris Power, Kay-Tee Khaw, Daniel Chasman, Paul Ridker, Torben Hansen, Keri L Monda, Thomas Illig, Marjo-Riitta Järvelin, Nicholas J Wareham, Frank B Hu, Leif C Groop, Marju Orho-Melander, Ulf Ekelund, Paul W Franks, Ruth J F Loos.
PLoS Med.
PUBLISHED: 04-21-2011
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The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n?=?218,166) and nine studies of children and adolescents (n?=?19,268).
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Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.
Nat. Genet.
PUBLISHED: 04-12-2011
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We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.
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Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women.
Obesity (Silver Spring)
PUBLISHED: 10-21-2010
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Increased values of multiple adiposity-related anthropometric traits are important risk factors for many common complex diseases. We performed a genome-wide association (GWA) study for four quantitative traits related to body size and adiposity (BMI, weight, waist circumference, and height) in a cohort of 1,792 adult Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). This is the first GWA study of anthropometric traits in Filipinos, a population experiencing a rapid transition into a more obesogenic environment. In addition to identifying suggestive evidence of additional single-nucleotide polymorphism (SNP) association signals (P < 10(-5)), we replicated (P < 0.05, same direction of additive effect) associations previously reported in European populations of both BMI and weight with MC4R and FTO, of BMI with BDNF, and of height with EFEMP1, ZBTB38, and NPPC, but none with waist circumference. We also replicated loci reported in Japanese or Korean populations as associated with BMI (OTOL1) and height (HIST1H1PS2, C14orf145, GPC5). A difference in local linkage disequilibrium (LD) between European and Asian populations suggests a narrowed association region for BDNF, while still including a proposed functional nonsynonymous amino acid substitution variant (rs6265, Val66Met). Finally, we observed significant evidence (P < 0.0042) for age-by-genotype interactions influencing BMI for rs17782313 (MC4R) and rs9939609 (FTO), and for a study year-by-genotype interaction for rs4923461 (BDNF). Our results show that several genetic risk factors are associated with anthropometric traits in Filipinos and provide further insight into the effects of BDNF, FTO, and MC4R on BMI.
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Genome-wide association study for adiponectin levels in Filipino women identifies CDH13 and a novel uncommon haplotype at KNG1-ADIPOQ.
Hum. Mol. Genet.
PUBLISHED: 09-27-2010
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Adiponectin is an adipocyte-secreted protein involved in a variety of metabolic processes, including glucose regulation and fatty acid catabolism. We conducted a genome-wide association study to investigate the genetic loci associated with plasma adiponectin in 1776 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). Our strongest signal for adiponectin mapped to the gene CDH13 (rs3865188, P ? 7.2 × 10(-16)), which encodes a receptor for high-molecular-weight forms of adiponectin. Strong association was also detected near the ADIPOQ gene (rs864265, P = 3.8 × 10(-9)) and at a novel signal 100 kb upstream near KNG1 (rs11924390, P = 7.6 × 10(-7)). All three signals were also observed in 1774 young adult CLHNS offspring and in combined analysis including all 3550 mothers and offspring samples (all P ? 1.6 × 10(-9)). An uncommon haplotype of rs11924390 and rs864265 (haplotype frequency = 0.050) was strongly associated with lower adiponectin compared with the most common C-G haplotype in both CLHNS mothers (P = 1.8 × 10(-25)) and offspring (P = 8.7 × 10(-32)). Comprehensive imputation of 2653 SNPs in a 2 Mb region using as reference combined CHB, JPT and CEU haplotypes from the 1000 Genomes Project revealed no variants that perfectly tagged this haplotype. Our findings provide the first genome-wide significant evidence of association with plasma adiponectin at the CDH13 locus and identify a novel uncommon KNG1-ADIPOQ haplotype strongly associated with adiponectin levels in Filipinos.
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Genetic variants influencing circulating lipid levels and risk of coronary artery disease.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 09-23-2010
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Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.
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Common variants at 10 genomic loci influence hemoglobin A?(C) levels via glycemic and nonglycemic pathways.
Nicole Soranzo, Serena Sanna, Eleanor Wheeler, Christian Gieger, Dörte Radke, Josée Dupuis, Nabila Bouatia-Naji, Claudia Langenberg, Inga Prokopenko, Elliot Stolerman, Manjinder S Sandhu, Matthew M Heeney, Joseph M Devaney, Muredach P Reilly, Sally L Ricketts, Alexandre F R Stewart, Benjamin F Voight, Christina Willenborg, Benjamin Wright, David Altshuler, Dan Arking, Beverley Balkau, Daniel Barnes, Eric Boerwinkle, Bernhard Böhm, Amélie Bonnefond, Lori L Bonnycastle, Dorret I Boomsma, Stefan R Bornstein, Yvonne Böttcher, Suzannah Bumpstead, Mary Susan Burnett-Miller, Harry Campbell, Antonio Cao, John Chambers, Robert Clark, Francis S Collins, Josef Coresh, Eco J C de Geus, Mariano Dei, Panos Deloukas, Angela Döring, Josephine M Egan, Roberto Elosua, Luigi Ferrucci, Nita Forouhi, Caroline S Fox, Christopher Franklin, Maria Grazia Franzosi, Sophie Gallina, Anuj Goel, Jurgen Graessler, Harald Grallert, Andreas Greinacher, David Hadley, Alistair Hall, Anders Hamsten, Caroline Hayward, Simon Heath, Christian Herder, Georg Homuth, Jouke-Jan Hottenga, Rachel Hunter-Merrill, Thomas Illig, Anne U Jackson, Antti Jula, Marcus Kleber, Christopher W Knouff, Augustine Kong, Jaspal Kooner, Anna Köttgen, Peter Kovacs, Knut Krohn, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Mark Lathrop, Cécile Lecoeur, Man Li, Mingyao Li, Ruth J F Loos, Jian'an Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K E Magnusson, Anders Malarstig, Massimo Mangino, María Teresa Martínez-Larrad, Winfried März, Wendy L McArdle, Ruth McPherson, Christa Meisinger, Thomas Meitinger, Olle Melander, Karen L Mohlke, Vincent E Mooser, Mario A Morken, Narisu Narisu, David M Nathan, Matthias Nauck, Chris O'Donnell, Konrad Oexle, Nazario Olla, James S Pankow, Felicity Payne, John F Peden, Nancy L Pedersen, Leena Peltonen, Markus Perola, Ozren Polašek, Eleonora Porcu, Daniel J Rader, Wolfgang Rathmann, Samuli Ripatti, Ghislain Rocheleau, Michael Roden, Igor Rudan, Veikko Salomaa, Richa Saxena, David Schlessinger, Heribert Schunkert, Peter Schwarz, Udo Seedorf, Elizabeth Selvin, Manuel Serrano-Ríos, Peter Shrader, Angela Silveira, David Siscovick, Kjioung Song, Timothy D Spector, Kari Stefansson, Valgerdur Steinthorsdottir, David P Strachan, Rona Strawbridge, Michael Stumvoll, Ida Surakka, Amy J Swift, Toshiko Tanaka, Alexander Teumer, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Anke Tönjes, Gianluca Usala, Veronique Vitart, Henry Völzke, Henri Wallaschofski, Dawn M Waterworth, Hugh Watkins, H-Erich Wichmann, Sarah H Wild, Gonneke Willemsen, Gordon H Williams, James F Wilson, Juliane Winkelmann, Alan F Wright, , Carina Zabena, Jing Hua Zhao, Stephen E Epstein, Jeanette Erdmann, Hakon H Hakonarson, Sekar Kathiresan, Kay-Tee Khaw, Robert Roberts, Nilesh J Samani, Mark D Fleming, Robert Sladek, Goncalo Abecasis, Michael Boehnke, Philippe Froguel, Leif Groop, Mark I McCarthy, W H Linda Kao, Jose C Florez, Manuela Uda, Nicholas J Wareham, Inês Barroso, James B Meigs.
Diabetes
PUBLISHED: 09-21-2010
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Glycated hemoglobin (HbA?(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA?(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA?(c) levels.
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Spontaneous Irs1 passenger mutation linked to a gene-targeted SerpinB2 allele.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-13-2010
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In characterizing mice with targeted disruption of the SerpinB2 gene, we observed animals that were small at birth with delayed growth and decreased life expectancy. Although this phenotype cosegregated with homozygosity for the inactive SerpinB2 allele, analysis of homozygous SerpinB2-deficient mice derived from two additional independent embryonic stem (ES) cell clones exhibited no growth abnormalities. Examination of additional progeny from the original SerpinB2-deficient line revealed recombination between the small phenotype (smla) and the SerpinB2 locus. The locus responsible for smla was mapped to a 2.78-Mb interval approximately 30 Mb proximal to SerpinB2, bounded by markers D1Mit382 and D1Mit216. Sequencing of Irs1 identified a nonsense mutation at serine 57 (S57X), resulting in complete loss of IRS1 protein expression. Analysis of ES cell DNA suggests that the S57X Irs1 mutation arose spontaneously in an ES cell subclone during cell culture. Although the smla phenotype is similar to previously reported Irs1 alleles, mice exhibited decreased survival, in contrast to the enhanced longevity reported for IRS1 deficiency generated by gene targeting. This discrepancy could result from differences in strain background, unintended indirect effects of the gene targeting, or the minimal genetic interference of the S57X mutation compared with the conventionally targeted Irs1-KO allele. Spontaneous mutations arising during ES cell culture may be a frequent but underappreciated occurrence. When linked to a targeted allele, such mutations could lead to incorrect assignment of phenotype and may account for a subset of markedly discordant results from experiments independently targeting the same gene.
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
Elizabeth K Speliotes, Cristen J Willer, Sonja I Berndt, Keri L Monda, Gudmar Thorleifsson, Anne U Jackson, Hana Lango Allen, Cecilia M Lindgren, Jian'an Luan, Reedik Mägi, Joshua C Randall, Sailaja Vedantam, Thomas W Winkler, Lu Qi, Tsegaselassie Workalemahu, Iris M Heid, Valgerdur Steinthorsdottir, Heather M Stringham, Michael N Weedon, Eleanor Wheeler, Andrew R Wood, Teresa Ferreira, Robert J Weyant, Ayellet V Segrè, Karol Estrada, Liming Liang, James Nemesh, Ju-Hyun Park, Stefan Gustafsson, Tuomas O Kilpeläinen, Jian Yang, Nabila Bouatia-Naji, Tonu Esko, Mary F Feitosa, Zoltan Kutalik, Massimo Mangino, Soumya Raychaudhuri, André Scherag, Albert Vernon Smith, Ryan Welch, Jing Hua Zhao, Katja K Aben, Devin M Absher, Najaf Amin, Anna L Dixon, Eva Fisher, Nicole L Glazer, Michael E Goddard, Nancy L Heard-Costa, Volker Hoesel, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Shamika Ketkar, Claudia Lamina, Shengxu Li, Miriam F Moffatt, Richard H Myers, Narisu Narisu, John R B Perry, Marjolein J Peters, Michael Preuss, Samuli Ripatti, Fernando Rivadeneira, Camilla Sandholt, Laura J Scott, Nicholas J Timpson, Jonathan P Tyrer, Sophie van Wingerden, Richard M Watanabe, Charles C White, Fredrik Wiklund, Christina Barlassina, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Robert W Lawrence, Niina Pellikka, Inga Prokopenko, Jianxin Shi, Elisabeth Thiering, Helene Alavere, Maria T S Alibrandi, Peter Almgren, Alice M Arnold, Thor Aspelund, Larry D Atwood, Beverley Balkau, Anthony J Balmforth, Amanda J Bennett, Yoav Ben-Shlomo, Richard N Bergman, Sven Bergmann, Heike Biebermann, Alexandra I F Blakemore, Tanja Boes, Lori L Bonnycastle, Stefan R Bornstein, Morris J Brown, Thomas A Buchanan, Fabio Busonero, Harry Campbell, Francesco P Cappuccio, Christine Cavalcanti-Proença, Yii-Der Ida Chen, Chih-Mei Chen, Peter S Chines, Robert Clarke, Lachlan Coin, John Connell, Ian N M Day, Martin den Heijer, Jubao Duan, Shah Ebrahim, Paul Elliott, Roberto Elosua, Gudny Eiriksdottir, Michael R Erdos, Johan G Eriksson, Maurizio F Facheris, Stephan B Felix, Pamela Fischer-Posovszky, Aaron R Folsom, Nele Friedrich, Nelson B Freimer, Mao Fu, Stefan Gaget, Pablo V Gejman, Eco J C Geus, Christian Gieger, Anette P Gjesing, Anuj Goel, Philippe Goyette, Harald Grallert, Jürgen Gräßler, Danielle M Greenawalt, Christopher J Groves, Vilmundur Gudnason, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Alistair S Hall, Aki S Havulinna, Caroline Hayward, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Anke Hinney, Albert Hofman, Georg Homuth, Jennie Hui, Wilmar Igl, Carlos Iribarren, Bo Isomaa, Kevin B Jacobs, Ivonne Jarick, Elizabeth Jewell, Ulrich John, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Marika Kaakinen, Eero Kajantie, Lee M Kaplan, Sekar Kathiresan, Johannes Kettunen, Leena Kinnunen, Joshua W Knowles, Ivana Kolčić, Inke R König, Seppo Koskinen, Peter Kovacs, Johanna Kuusisto, Peter Kraft, Kirsti Kvaløy, Jaana Laitinen, Olivier Lantieri, Chiara Lanzani, Lenore J Launer, Cécile Lecoeur, Terho Lehtimäki, Guillaume Lettre, Jianjun Liu, Marja-Liisa Lokki, Mattias Lorentzon, Robert N Luben, Barbara Ludwig, , Paolo Manunta, Diana Marek, Michel Marre, Nicholas G Martin, Wendy L McArdle, Anne McCarthy, Barbara McKnight, Thomas Meitinger, Olle Melander, David Meyre, Kristian Midthjell, Grant W Montgomery, Mario A Morken, Andrew P Morris, Rosanda Mulić, Julius S Ngwa, Mari Nelis, Matt J Neville, Dale R Nyholt, Christopher J O'Donnell, Stephen O'Rahilly, Ken K Ong, Ben Oostra, Guillaume Paré, Alex N Parker, Markus Perola, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Ozren Polašek, Anneli Pouta, Suzanne Rafelt, Olli Raitakari, Nigel W Rayner, Martin Ridderstråle, Winfried Rief, Aimo Ruokonen, Neil R Robertson, Peter Rzehak, Veikko Salomaa, Alan R Sanders, Manjinder S Sandhu, Serena Sanna, Jouko Saramies, Markku J Savolainen, Susann Scherag, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, Kaisa Silander, Juha Sinisalo, David S Siscovick, Jan H Smit, Nicole Soranzo, Ulla Sovio, Jonathan Stephens, Ida Surakka, Amy J Swift, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Tanya M Teslovich, John R Thompson, Brian Thomson, Anke Tönjes, Tiinamaija Tuomi, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Jorma Viikari, Sophie Visvikis-Siest, Veronique Vitart, Carla I G Vogel, Benjamin F Voight, Lindsay L Waite, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Susanna Wiegand, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Jacqueline C Witteman, Jianfeng Xu, Qunyuan Zhang, Lina Zgaga, Andreas Ziegler, Paavo Zitting, John P Beilby, I Sadaf Farooqi, Johannes Hebebrand, Heikki V Huikuri, Alan L James, Mika Kähönen, Douglas F Levinson, Fabio Macciardi, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Paul M Ridker, Michael Stumvoll, Jacques S Beckmann, Heiner Boeing, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, Francis S Collins, L Adrienne Cupples, George Davey Smith, Jeanette Erdmann, Philippe Froguel, Henrik Grönberg, Ulf Gyllensten, Per Hall, Torben Hansen, Tamara B Harris, Andrew T Hattersley, Richard B Hayes, Joachim Heinrich, Frank B Hu, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Jaakko Kaprio, Fredrik Karpe, Kay-Tee Khaw, Lambertus A Kiemeney, Heiko Krude, Markku Laakso, Debbie A Lawlor, Andres Metspalu, Patricia B Munroe, Willem H Ouwehand, Oluf Pedersen, Brenda W Penninx, Annette Peters, Peter P Pramstaller, Thomas Quertermous, Thomas Reinehr, Aila Rissanen, Igor Rudan, Nilesh J Samani, Peter E H Schwarz, Alan R Shuldiner, Timothy D Spector, Jaakko Tuomilehto, Manuela Uda, André Uitterlinden, Timo T Valle, Martin Wabitsch, Gérard Waeber, Nicholas J Wareham, Hugh Watkins, James F Wilson, Alan F Wright, M Carola Zillikens, Nilanjan Chatterjee, Steven A McCarroll, Shaun Purcell, Eric E Schadt, Peter M Visscher, Themistocles L Assimes, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Karen L Mohlke, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Cornelia M van Duijn, H-Erich Wichmann, Timothy M Frayling, Unnur Thorsteinsdottir, Gonçalo R Abecasis, Inês Barroso, Michael Boehnke, Kari Stefansson, Kari E North, Mark I McCarthy, Joel N Hirschhorn, Erik Ingelsson, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 05-13-2010
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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ? 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
Iris M Heid, Anne U Jackson, Joshua C Randall, Thomas W Winkler, Lu Qi, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, M Carola Zillikens, Elizabeth K Speliotes, Reedik Mägi, Tsegaselassie Workalemahu, Charles C White, Nabila Bouatia-Naji, Tamara B Harris, Sonja I Berndt, Erik Ingelsson, Cristen J Willer, Michael N Weedon, Jian'an Luan, Sailaja Vedantam, Tonu Esko, Tuomas O Kilpeläinen, Zoltan Kutalik, Shengxu Li, Keri L Monda, Anna L Dixon, Christopher C Holmes, Lee M Kaplan, Liming Liang, Josine L Min, Miriam F Moffatt, Cliona Molony, George Nicholson, Eric E Schadt, Krina T Zondervan, Mary F Feitosa, Teresa Ferreira, Hana Lango Allen, Robert J Weyant, Eleanor Wheeler, Andrew R Wood, , Karol Estrada, Michael E Goddard, Guillaume Lettre, Massimo Mangino, Dale R Nyholt, Shaun Purcell, Albert Vernon Smith, Peter M Visscher, Jian Yang, Steven A McCarroll, James Nemesh, Benjamin F Voight, Devin Absher, Najaf Amin, Thor Aspelund, Lachlan Coin, Nicole L Glazer, Caroline Hayward, Nancy L Heard-Costa, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Marika Kaakinen, Karen Kapur, Shamika Ketkar, Joshua W Knowles, Peter Kraft, Aldi T Kraja, Claudia Lamina, Michael F Leitzmann, Barbara McKnight, Andrew P Morris, Ken K Ong, John R B Perry, Marjolein J Peters, Ozren Polašek, Inga Prokopenko, Nigel W Rayner, Samuli Ripatti, Fernando Rivadeneira, Neil R Robertson, Serena Sanna, Ulla Sovio, Ida Surakka, Alexander Teumer, Sophie van Wingerden, Veronique Vitart, Jing Hua Zhao, Christine Cavalcanti-Proença, Peter S Chines, Eva Fisher, Jennifer R Kulzer, Cécile Lecoeur, Narisu Narisu, Camilla Sandholt, Laura J Scott, Kaisa Silander, Klaus Stark, Mari-Liis Tammesoo, Tanya M Teslovich, Nicholas John Timpson, Richard M Watanabe, Ryan Welch, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Johannes Kettunen, Robert W Lawrence, Niina Pellikka, Markus Perola, Liesbeth Vandenput, Helene Alavere, Peter Almgren, Larry D Atwood, Amanda J Bennett, Reiner Biffar, Lori L Bonnycastle, Stefan R Bornstein, Thomas A Buchanan, Harry Campbell, Ian N M Day, Mariano Dei, Marcus Dörr, Paul Elliott, Michael R Erdos, Johan G Eriksson, Nelson B Freimer, Mao Fu, Stefan Gaget, Eco J C Geus, Anette P Gjesing, Harald Grallert, Jürgen Gräßler, Christopher J Groves, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Aki S Havulinna, Karl-Heinz Herzig, Andrew A Hicks, Jennie Hui, Wilmar Igl, Pekka Jousilahti, Antti Jula, Eero Kajantie, Leena Kinnunen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Heyo K Kroemer, Vjekoslav Krželj, Johanna Kuusisto, Kirsti Kvaloy, Jaana Laitinen, Olivier Lantieri, G Mark Lathrop, Marja-Liisa Lokki, Robert N Luben, Barbara Ludwig, Wendy L McArdle, Anne McCarthy, Mario A Morken, Mari Nelis, Matt J Neville, Guillaume Paré, Alex N Parker, John F Peden, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Anneli Pouta, Martin Ridderstråle, Nilesh J Samani, Jouko Saramies, Juha Sinisalo, Jan H Smit, Rona J Strawbridge, Heather M Stringham, Amy J Swift, Maris Teder-Laving, Brian Thomson, Gianluca Usala, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Claudia B Volpato, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Lina Zgaga, Paavo Zitting, John P Beilby, Alan L James, Mika Kähönen, Terho Lehtimäki, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Olli Raitakari, Paul M Ridker, Michael Stumvoll, Anke Tönjes, Jorma Viikari, Beverley Balkau, Yoav Ben-Shlomo, Richard N Bergman, Heiner Boeing, George Davey Smith, Shah Ebrahim, Philippe Froguel, Torben Hansen, Christian Hengstenberg, Kristian Hveem, Bo Isomaa, Torben Jørgensen, Fredrik Karpe, Kay-Tee Khaw, Markku Laakso, Debbie A Lawlor, Michel Marre, Thomas Meitinger, Andres Metspalu, Kristian Midthjell, Oluf Pedersen, Veikko Salomaa, Peter E H Schwarz, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T Valle, Nicholas J Wareham, Alice M Arnold, Jacques S Beckmann, Sven Bergmann, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Francis S Collins, Gudny Eiriksdottir, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Andrew T Hattersley, Albert Hofman, Frank B Hu, Thomas Illig, Carlos Iribarren, Marjo-Riitta Järvelin, W H Linda Kao, Jaakko Kaprio, Lenore J Launer, Patricia B Munroe, Ben Oostra, Brenda W Penninx, Peter P Pramstaller, Bruce M Psaty, Thomas Quertermous, Aila Rissanen, Igor Rudan, Alan R Shuldiner, Nicole Soranzo, Timothy D Spector, Ann-Christine Syvänen, Manuela Uda, André Uitterlinden, Henry Völzke, Peter Vollenweider, James F Wilson, Jacqueline C Witteman, Alan F Wright, Gonçalo R Abecasis, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Timothy M Frayling, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Kari E North, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Joel N Hirschhorn, Themistocles L Assimes, H-Erich Wichmann, Unnur Thorsteinsdottir, Cornelia M van Duijn, Kari Stefansson, L Adrienne Cupples, Ruth J F Loos, Inês Barroso, Mark I McCarthy, Caroline S Fox, Karen L Mohlke, Cecilia M Lindgren.
Nat. Genet.
PUBLISHED: 05-06-2010
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Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?³ to P = 1.2 × 10?¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hana Lango Allen, Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tonu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltan Kutalik, Keri L Monda, Ozren Polašek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marušić, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Järvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn.
Nature
PUBLISHED: 04-23-2010
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Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?
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Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
Nat. Genet.
PUBLISHED: 03-17-2010
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To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
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Biological, clinical and population relevance of 95 loci for blood lipids.
Tanya M Teslovich, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Samuli Ripatti, Daniel I Chasman, Cristen J Willer, Christopher T Johansen, Sigrid W Fouchier, Aaron Isaacs, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Yurii S Aulchenko, Gudmar Thorleifsson, Mary F Feitosa, John Chambers, Marju Orho-Melander, Olle Melander, Toby Johnson, Xiaohui Li, Xiuqing Guo, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Kijoung Song, Jing Hua Zhao, Xin Yuan, Jian'an Luan, Claudia Lamina, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, Alan F Wright, Jacqueline C M Witteman, James F Wilson, Gonneke Willemsen, H-Erich Wichmann, John B Whitfield, Dawn M Waterworth, Nicholas J Wareham, Gérard Waeber, Peter Vollenweider, Benjamin F Voight, Veronique Vitart, André G Uitterlinden, Manuela Uda, Jaakko Tuomilehto, John R Thompson, Toshiko Tanaka, Ida Surakka, Heather M Stringham, Tim D Spector, Nicole Soranzo, Johannes H Smit, Juha Sinisalo, Kaisa Silander, Eric J G Sijbrands, Angelo Scuteri, James Scott, David Schlessinger, Serena Sanna, Veikko Salomaa, Juha Saharinen, Chiara Sabatti, Aimo Ruokonen, Igor Rudan, Lynda M Rose, Robert Roberts, Mark Rieder, Bruce M Psaty, Peter P Pramstaller, Irene Pichler, Markus Perola, Brenda W J H Penninx, Nancy L Pedersen, Cristian Pattaro, Alex N Parker, Guillaume Paré, Ben A Oostra, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Thomas Meitinger, Ruth McPherson, Mark I McCarthy, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Massimo Mangino, Patrik K E Magnusson, Gavin Lucas, Robert Luben, Ruth J F Loos, Marja-Liisa Lokki, Guillaume Lettre, Claudia Langenberg, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Florian Kronenberg, Inke R König, Kay-Tee Khaw, Jaakko Kaprio, Lee M Kaplan, Asa Johansson, Marjo-Riitta Järvelin, A Cecile J W Janssens, Erik Ingelsson, Wilmar Igl, G Kees Hovingh, Jouke-Jan Hottenga, Albert Hofman, Andrew A Hicks, Christian Hengstenberg, Iris M Heid, Caroline Hayward, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Ulf Gyllensten, Candace Guiducci, Leif C Groop, Elena González, Christian Gieger, Nelson B Freimer, Luigi Ferrucci, Jeanette Erdmann, Paul Elliott, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Eco J C de Geus, Ulf de Faire, Gabriel Crawford, Francis S Collins, Yii-Der I Chen, Mark J Caulfield, Harry Campbell, Noel P Burtt, Lori L Bonnycastle, Dorret I Boomsma, S Matthijs Boekholdt, Richard N Bergman, Inês Barroso, Stefania Bandinelli, Christie M Ballantyne, Themistocles L Assimes, Thomas Quertermous, David Altshuler, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Linda S Adair, Herman A Taylor, Ingrid B Borecki, Stacey B Gabriel, James G Wilson, Hilma Holm, Unnur Thorsteinsdottir, Vilmundur Gudnason, Ronald M Krauss, Karen L Mohlke, José M Ordovás, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, Jerome I Rotter, Eric Boerwinkle, David P Strachan, Vincent Mooser, Kari Stefansson, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Cornelia M van Duijn, Leena Peltonen, Gonçalo R Abecasis, Michael Boehnke, Sekar Kathiresan.
Nature
PUBLISHED: 02-25-2010
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Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.
Diabetes
PUBLISHED: 02-25-2010
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OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
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Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK.
Hum. Mol. Genet.
PUBLISHED: 02-16-2010
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Genome-wide association studies (GWAS) have identified numerous loci associated with various complex traits for which the underlying susceptibility gene(s) remain unknown. In a GWAS for high-density lipoprotein-cholesterol (HDL-C) level, one strongly associated locus contains at least two biologically compelling candidates, methylmalonic aciduria cblB type (MMAB) and mevalonate kinase (MVK). To detect evidence of cis-acting regulation at this locus, we measured relative allelic expression of transcribed SNPs in five genes using human hepatocyte samples heterozygous for the transcribed SNP. If an HDL-C-associated SNP allele differentially regulates mRNA level in cis, samples heterozygous both for a transcribed SNP and an HDL-C-associated SNP should display allelic expression imbalance (AEI) of the transcribed SNP. We designed statistical tests to detect AEI in a comprehensive set of linkage disequilibrium (LD) scenarios between the transcribed SNP and an HDL-C-associated SNP (rs7298565) in phase unknown samples. We observed significant AEI of 22% in MMAB (P = 1.4 x 10(-13), transcribed SNP rs11067231), and the allele associated with lower HDL-C level was associated with greater MMAB transcript level. The same rs7298565 allele was also associated with higher MMAB mRNA level (P = 0.0081) and higher MMAB protein level (P = 0.0020). In contrast, MVK, UBE3B, KCTD10 and ACACB did not show significant AEI (P > or = 0.05). These data suggest MMAB is the most likely gene influencing HDL-C levels at this locus and demonstrate that measuring AEI at loci containing more than one candidate gene can prioritize genes for functional studies.
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Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults.
Hum. Mol. Genet.
PUBLISHED: 02-13-2010
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Plasma homocysteine (Hcy) level is associated with cardiovascular disease and may play an etiologic role in vascular damage, a precursor for atherosclerosis. We performed a genome-wide association study for Hcy in 1786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP) (rs7422339, P = 4.7 x 10(-13)) encodes Thr1405Asn in the gene CPS1 and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133) was also highly significant (P = 8.7 x 10(-10)) and explained 1.6% of the trait variation. We also genotyped these two SNPs in 1679 CLHNS young adult offspring. The MTHFR C677T SNP was strongly associated with Hcy (P = 1.9 x 10(-26)) and explained approximately 5.1% of the variation in the offspring. In contrast, the CPS1 variant was significant only in females (P = 0.11 in all; P = 0.0087 in females). Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring (interaction P = 1.2 x 10(-5)). Furthermore, although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring (interaction P = 0.0046), there was no significant evidence for an interaction in the mothers (P = 0.55). These data confirm a recent finding that CPS1 is a locus influencing Hcy levels in women and suggest that genetic effects on Hcy may differ across developmental stages.
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A map of open chromatin in human pancreatic islets.
Nat. Genet.
PUBLISHED: 01-31-2010
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Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified approximately 80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed approximately 3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.
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Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noisël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, .
Nat. Genet.
PUBLISHED: 01-19-2010
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By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U Jackson, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Anna L Gloyn, Cecilia M Lindgren, Reedik Mägi, Andrew P Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter Henneman, Harald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R B Perry, Josephine M Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F Voight, Heather M Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Felicity Payne, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Kristin Ardlie, Yavuz Ariyurek, Beverley Balkau, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Rafn Benediktsson, Amanda J Bennett, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Guillaume Charpentier, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Marilyn Cornelis, Gabe Crawford, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Christian Dina, Michael R Erdos, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Caroline S Fox, Rune Frants, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Christopher J Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, Samy Hadjadj, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Neelam Hassanali, Caroline Hayward, Simon C Heath, Serge Hercberg, Christian Herder, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Albert Hofman, Jennie Hui, Joe Hung, Bo Isomaa, Paul R V Johnson, Torben Jørgensen, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Valeriya Lyssenko, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Laura J McCulloch, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Mario A Morken, Sutapa Mukherjee, Silvia Naitza, Narisu Narisu, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Colin N A Palmer, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Wolfgang Rathmann, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Michael Roden, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Laura J Scott, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurethsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Barbara Thorand, Jean Tichet, Anke Tönjes, Tiinamaija Tuomi, André G Uitterlinden, Ko Willems van Dijk, Mandy van Hoek, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, G Bragi Walters, Kim L Ward, Hugh Watkins, Michael N Weedon, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Eleftheria Zeggini, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, , Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Andrew T Hattersley, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Andrew D Morris, Lars Lind, Lyle J Palmer, Frank B Hu, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, James S Pankow, Michael J Sampson, Johanna Kuusisto, Markku Laakso, Torben Hansen, Oluf Pedersen, Peter Paul Pramstaller, H Erich Wichmann, Thomas Illig, Igor Rudan, Alan F Wright, Michael Stumvoll, Harry Campbell, James F Wilson, Richard N Bergman, Thomas A Buchanan, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Timo T Valle, David Altshuler, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Timothy M Frayling, Luigi Ferrucci, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Cornelia M van Duijn, Yurii S Aulchenko, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Gonçalo R Abecasis, Nicholas J Wareham, Robert Sladek, Philippe Froguel, Richard M Watanabe, James B Meigs, Leif Groop, Michael Boehnke, Mark I McCarthy, Jose C Florez, Inês Barroso.
Nat. Genet.
PUBLISHED: 01-17-2010
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Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.
Richa Saxena, Marie-France Hivert, Claudia Langenberg, Toshiko Tanaka, James S Pankow, Peter Vollenweider, Valeriya Lyssenko, Nabila Bouatia-Naji, Josée Dupuis, Anne U Jackson, W H Linda Kao, Man Li, Nicole L Glazer, Alisa K Manning, Jian'an Luan, Heather M Stringham, Inga Prokopenko, Toby Johnson, Niels Grarup, Trine W Boesgaard, Cécile Lecoeur, Peter Shrader, Jeffrey O'Connell, Erik Ingelsson, David J Couper, Kenneth Rice, Kijoung Song, Camilla H Andreasen, Christian Dina, Anna Köttgen, Olivier Le Bacquer, François Pattou, Jalal Taneera, Valgerdur Steinthorsdottir, Denis Rybin, Kristin Ardlie, Michael Sampson, Lu Qi, Mandy van Hoek, Michael N Weedon, Yurii S Aulchenko, Benjamin F Voight, Harald Grallert, Beverley Balkau, Richard N Bergman, Suzette J Bielinski, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Thomas A Buchanan, Suzannah J Bumpstead, Christine Cavalcanti-Proença, Guillaume Charpentier, Yii-Der Ida Chen, Peter S Chines, Francis S Collins, Marilyn Cornelis, Gabriel J Crawford, Jérôme Delplanque, Alex Doney, Josephine M Egan, Michael R Erdos, Mathieu Firmann, Nita G Forouhi, Caroline S Fox, Mark O Goodarzi, Jurgen Graessler, Aroon Hingorani, Bo Isomaa, Torben Jørgensen, Mika Kivimäki, Peter Kovacs, Knut Krohn, Meena Kumari, Torsten Lauritzen, Claire Levy-Marchal, Vladimir Mayor, Jarred B McAteer, David Meyre, Braxton D Mitchell, Karen L Mohlke, Mario A Morken, Narisu Narisu, Colin N A Palmer, Ruth Pakyz, Laura Pascoe, Felicity Payne, Daniel Pearson, Wolfgang Rathmann, Annelli Sandbaek, Avan Aihie Sayer, Laura J Scott, Stephen J Sharp, Eric Sijbrands, Andrew Singleton, David S Siscovick, Nicholas L Smith, Thomas Sparsø, Amy J Swift, Holly Syddall, Gudmar Thorleifsson, Anke Tönjes, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T Valle, Gérard Waeber, Andrew Walley, Dawn M Waterworth, Eleftheria Zeggini, Jing Hua Zhao, , Thomas Illig, H Erich Wichmann, James F Wilson, Cornelia van Duijn, Frank B Hu, Andrew D Morris, Timothy M Frayling, Andrew T Hattersley, Unnur Thorsteinsdottir, Kari Stefansson, Peter Nilsson, Ann-Christine Syvänen, Alan R Shuldiner, Mark Walker, Stefan R Bornstein, Peter Schwarz, Gordon H Williams, David M Nathan, Johanna Kuusisto, Markku Laakso, Cyrus Cooper, Michael Marmot, Luigi Ferrucci, Vincent Mooser, Michael Stumvoll, Ruth J F Loos, David Altshuler, Bruce M Psaty, Jerome I Rotter, Eric Boerwinkle, Torben Hansen, Oluf Pedersen, Jose C Florez, Mark I McCarthy, Michael Boehnke, Inês Barroso, Robert Sladek, Philippe Froguel, James B Meigs, Leif Groop, Nicholas J Wareham, Richard M Watanabe.
Nat. Genet.
PUBLISHED: 01-17-2010
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Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
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Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?
PLoS Genet.
PUBLISHED: 09-22-2009
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The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (healthy population, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.
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Genome-wide association study identifies eight loci associated with blood pressure.
Christopher Newton-Cheh, Toby Johnson, Vesela Gateva, Martin D Tobin, Murielle Bochud, Lachlan Coin, Samer S Najjar, Jing Hua Zhao, Simon C Heath, Susana Eyheramendy, Konstantinos Papadakis, Benjamin F Voight, Laura J Scott, Feng Zhang, Martin Farrall, Toshiko Tanaka, Chris Wallace, John C Chambers, Kay-Tee Khaw, Peter Nilsson, Pim van der Harst, Silvia Polidoro, Diederick E Grobbee, N Charlotte Onland-Moret, Michiel L Bots, Louise V Wain, Katherine S Elliott, Alexander Teumer, Jian'an Luan, Gavin Lucas, Johanna Kuusisto, Paul R Burton, David Hadley, Wendy L McArdle, , Morris Brown, Anna Dominiczak, Stephen J Newhouse, Nilesh J Samani, John Webster, Eleftheria Zeggini, Jacques S Beckmann, Sven Bergmann, Noha Lim, Kijoung Song, Peter Vollenweider, Gérard Waeber, Dawn M Waterworth, Xin Yuan, Leif Groop, Marju Orho-Melander, Alessandra Allione, Alessandra Di Gregorio, Simonetta Guarrera, Salvatore Panico, Fulvio Ricceri, Valeria Romanazzi, Carlotta Sacerdote, Paolo Vineis, Inês Barroso, Manjinder S Sandhu, Robert N Luben, Gabriel J Crawford, Pekka Jousilahti, Markus Perola, Michael Boehnke, Lori L Bonnycastle, Francis S Collins, Anne U Jackson, Karen L Mohlke, Heather M Stringham, Timo T Valle, Cristen J Willer, Richard N Bergman, Mario A Morken, Angela Döring, Christian Gieger, Thomas Illig, Thomas Meitinger, Elin Org, Arne Pfeufer, H Erich Wichmann, Sekar Kathiresan, Jaume Marrugat, Christopher J O'Donnell, Stephen M Schwartz, David S Siscovick, Isaac Subirana, Nelson B Freimer, Anna-Liisa Hartikainen, Mark I McCarthy, Paul F O'Reilly, Leena Peltonen, Anneli Pouta, Paul E de Jong, Harold Snieder, Wiek H van Gilst, Robert Clarke, Anuj Goel, Anders Hamsten, John F Peden, Udo Seedorf, Ann-Christine Syvänen, Giovanni Tognoni, Edward G Lakatta, Serena Sanna, Paul Scheet, David Schlessinger, Angelo Scuteri, Marcus Dörr, Florian Ernst, Stephan B Felix, Georg Homuth, Roberto Lorbeer, Thorsten Reffelmann, Rainer Rettig, Uwe Völker, Pilar Galán, Ivo G Gut, Serge Hercberg, G Mark Lathrop, Diana Zelenika, Panos Deloukas, Nicole Soranzo, Frances M Williams, Guangju Zhai, Veikko Salomaa, Markku Laakso, Roberto Elosua, Nita G Forouhi, Henry Völzke, Cuno S Uiterwaal, Yvonne T van der Schouw, Mattijs E Numans, Giuseppe Matullo, Gerjan Navis, Göran Berglund, Sheila A Bingham, Jaspal S Kooner, John M Connell, Stefania Bandinelli, Luigi Ferrucci, Hugh Watkins, Tim D Spector, Jaakko Tuomilehto, David Altshuler, David P Strachan, Maris Laan, Pierre Meneton, Nicholas J Wareham, Manuela Uda, Marjo-Riitta Järvelin, Vincent Mooser, Olle Melander, Ruth J F Loos, Paul Elliott, Gonçalo R Abecasis, Mark Caulfield, Patricia B Munroe.
Nat. Genet.
PUBLISHED: 02-27-2009
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Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ? 71,225 European ancestry, N ? 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renstrom, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gérard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, , Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Järvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy.
PLoS Genet.
PUBLISHED: 02-18-2009
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To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis.
PLoS ONE
PUBLISHED: 02-13-2009
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Genome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16(INK4a), p15(INK4b), ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs.
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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.
Cristen J Willer, Elizabeth K Speliotes, Ruth J F Loos, Shengxu Li, Cecilia M Lindgren, Iris M Heid, Sonja I Berndt, Amanda L Elliott, Anne U Jackson, Claudia Lamina, Guillaume Lettre, Noha Lim, Helen N Lyon, Steven A McCarroll, Konstantinos Papadakis, Lu Qi, Joshua C Randall, Rosa Maria Roccasecca, Serena Sanna, Paul Scheet, Michael N Weedon, Eleanor Wheeler, Jing Hua Zhao, Leonie C Jacobs, Inga Prokopenko, Nicole Soranzo, Toshiko Tanaka, Nicholas J Timpson, Peter Almgren, Amanda Bennett, Richard N Bergman, Sheila A Bingham, Lori L Bonnycastle, Morris Brown, Noel P Burtt, Peter Chines, Lachlan Coin, Francis S Collins, John M Connell, Cyrus Cooper, George Davey Smith, Elaine M Dennison, Parimal Deodhar, Paul Elliott, Michael R Erdos, Karol Estrada, David M Evans, Lauren Gianniny, Christian Gieger, Christopher J Gillson, Candace Guiducci, Rachel Hackett, David Hadley, Alistair S Hall, Aki S Havulinna, Johannes Hebebrand, Albert Hofman, Bo Isomaa, Kevin B Jacobs, Toby Johnson, Pekka Jousilahti, Zorica Jovanović, Kay-Tee Khaw, Peter Kraft, Mikko Kuokkanen, Johanna Kuusisto, Jaana Laitinen, Edward G Lakatta, Jian'an Luan, Robert N Luben, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Antonella Mulas, Patricia B Munroe, Narisu Narisu, Andrew R Ness, Kate Northstone, Stephen O'Rahilly, Carolin Purmann, Matthew G Rees, Martin Ridderstråle, Susan M Ring, Fernando Rivadeneira, Aimo Ruokonen, Manjinder S Sandhu, Jouko Saramies, Laura J Scott, Angelo Scuteri, Kaisa Silander, Matthew A Sims, Kijoung Song, Jonathan Stephens, Suzanne Stevens, Heather M Stringham, Y C Loraine Tung, Timo T Valle, Cornelia M van Duijn, Karani S Vimaleswaran, Peter Vollenweider, Gérard Waeber, Chris Wallace, Richard M Watanabe, Dawn M Waterworth, Nicholas Watkins, , Jacqueline C M Witteman, Eleftheria Zeggini, Guangju Zhai, M Carola Zillikens, David Altshuler, Mark J Caulfield, Stephen J Chanock, I Sadaf Farooqi, Luigi Ferrucci, Jack M Guralnik, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Järvelin, Markku Laakso, Vincent Mooser, Ken K Ong, Willem H Ouwehand, Veikko Salomaa, Nilesh J Samani, Timothy D Spector, Tiinamaija Tuomi, Jaakko Tuomilehto, Manuela Uda, André G Uitterlinden, Nicholas J Wareham, Panagiotis Deloukas, Timothy M Frayling, Leif C Groop, Richard B Hayes, David J Hunter, Karen L Mohlke, Leena Peltonen, David Schlessinger, David P Strachan, H-Erich Wichmann, Mark I McCarthy, Michael Boehnke, Inês Barroso, Gonçalo R Abecasis, Joel N Hirschhorn.
Nat. Genet.
PUBLISHED: 01-24-2009
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Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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Variants in MTNR1B influence fasting glucose levels.
Inga Prokopenko, Claudia Langenberg, Jose C Florez, Richa Saxena, Nicole Soranzo, Gudmar Thorleifsson, Ruth J F Loos, Alisa K Manning, Anne U Jackson, Yurii Aulchenko, Simon C Potter, Michael R Erdos, Serena Sanna, Jouke-Jan Hottenga, Eleanor Wheeler, Marika Kaakinen, Valeriya Lyssenko, Wei-Min Chen, Kourosh Ahmadi, Jacques S Beckmann, Richard N Bergman, Murielle Bochud, Lori L Bonnycastle, Thomas A Buchanan, Antonio Cao, Alessandra Cervino, Lachlan Coin, Francis S Collins, Laura Crisponi, Eco J C de Geus, Abbas Dehghan, Panos Deloukas, Alex S F Doney, Paul Elliott, Nelson Freimer, Vesela Gateva, Christian Herder, Albert Hofman, Thomas E Hughes, Sarah Hunt, Thomas Illig, Michael Inouye, Bo Isomaa, Toby Johnson, Augustine Kong, Maria Krestyaninova, Johanna Kuusisto, Markku Laakso, Noha Lim, Ulf Lindblad, Cecilia M Lindgren, Owen T McCann, Karen L Mohlke, Andrew D Morris, Silvia Naitza, Marco Orrù, Colin N A Palmer, Anneli Pouta, Joshua Randall, Wolfgang Rathmann, Jouko Saramies, Paul Scheet, Laura J Scott, Angelo Scuteri, Stephen Sharp, Eric Sijbrands, Jan H Smit, Kijoung Song, Valgerdur Steinthorsdottir, Heather M Stringham, Tiinamaija Tuomi, Jaakko Tuomilehto, André G Uitterlinden, Benjamin F Voight, Dawn Waterworth, H-Erich Wichmann, Gonneke Willemsen, Jacqueline C M Witteman, Xin Yuan, Jing Hua Zhao, Eleftheria Zeggini, David Schlessinger, Manjinder Sandhu, Dorret I Boomsma, Manuela Uda, Tim D Spector, Brenda Wjh Penninx, David Altshuler, Peter Vollenweider, Marjo Riitta Jarvelin, Edward Lakatta, Gérard Waeber, Caroline S Fox, Leena Peltonen, Leif C Groop, Vincent Mooser, L Adrienne Cupples, Unnur Thorsteinsdottir, Michael Boehnke, Inês Barroso, Cornelia van Duijn, Josée Dupuis, Richard M Watanabe, Kari Stefansson, Mark I McCarthy, Nicholas J Wareham, James B Meigs, Gonçalo R Abecasis.
Nat. Genet.
PUBLISHED: 01-24-2009
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To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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Common variants at 30 loci contribute to polygenic dyslipidemia.
Nat. Genet.
PUBLISHED: 01-24-2009
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Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.
Nat. Genet.
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Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
Momoko Horikoshi, Hanieh Yaghootkar, Dennis O Mook-Kanamori, Ulla Sovio, H Rob Taal, Branwen J Hennig, Jonathan P Bradfield, Beate St Pourcain, David M Evans, Pimphen Charoen, Marika Kaakinen, Diana L Cousminer, Terho Lehtimäki, Eskil Kreiner-Møller, Nicole M Warrington, Mariona Bustamante, Bjarke Feenstra, Diane J Berry, Elisabeth Thiering, Thiemo Pfab, Sheila J Barton, Beverley M Shields, Marjan Kerkhof, Elisabeth M van Leeuwen, Anthony J Fulford, Zoltan Kutalik, Jing Hua Zhao, Marcel den Hoed, Anubha Mahajan, Virpi Lindi, Liang-Kee Goh, Jouke-Jan Hottenga, Ying Wu, Olli T Raitakari, Marie N Harder, Aline Meirhaeghe, Ioanna Ntalla, Rany M Salem, Karen A Jameson, Kaixin Zhou, Dorota M Monies, Vasiliki Lagou, Mirna Kirin, Jani Heikkinen, Linda S Adair, Fowzan S Alkuraya, Ali Al-Odaib, Philippe Amouyel, Ehm Astrid Andersson, Amanda J Bennett, Alexandra I F Blakemore, Jessica L Buxton, Jean Dallongeville, Shikta Das, Eco J C de Geus, Xavier Estivill, Claudia Flexeder, Philippe Froguel, Frank Geller, Keith M Godfrey, Frederic Gottrand, Christopher J Groves, Torben Hansen, Joel N Hirschhorn, Albert Hofman, Mads V Hollegaard, David M Hougaard, Elina Hyppönen, Hazel M Inskip, Aaron Isaacs, Torben Jørgensen, Christina Kanaka-Gantenbein, John P Kemp, Wieland Kiess, Tuomas O Kilpeläinen, Norman Klopp, Bridget A Knight, Christopher W Kuzawa, George McMahon, John P Newnham, Harri Niinikoski, Ben A Oostra, Louise Pedersen, Dirkje S Postma, Susan M Ring, Fernando Rivadeneira, Neil R Robertson, Sylvain Sebert, Olli Simell, Torsten Slowinski, Carla M T Tiesler, Anke Tönjes, Allan Vaag, Jorma S Viikari, Jacqueline M Vink, Nadja Hawwa Vissing, Nicholas J Wareham, Gonneke Willemsen, Daniel R Witte, Haitao Zhang, Jianhua Zhao, , James F Wilson, Michael Stumvoll, Andrew M Prentice, Brian F Meyer, Ewan R Pearson, Colin A G Boreham, Cyrus Cooper, Matthew W Gillman, George V Dedoussis, Luis A Moreno, Oluf Pedersen, Maiju Saarinen, Karen L Mohlke, Dorret I Boomsma, Seang-Mei Saw, Timo A Lakka, Antje Körner, Ruth J F Loos, Ken K Ong, Peter Vollenweider, Cornelia M van Duijn, Gerard H Koppelman, Andrew T Hattersley, John W Holloway, Berthold Hocher, Joachim Heinrich, Chris Power, Mads Melbye, Mònica Guxens, Craig E Pennell, Klaus Bønnelykke, Hans Bisgaard, Johan G Eriksson, Elisabeth Widén, Hakon Hakonarson, André G Uitterlinden, Anneli Pouta, Debbie A Lawlor, George Davey Smith, Timothy M Frayling, Mark I McCarthy, Struan F A Grant, Vincent W V Jaddoe, Marjo-Riitta Järvelin, Nicholas J Timpson, Inga Prokopenko, Rachel M Freathy.
Nat. Genet.
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Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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What will diabetes genomes tell us?
Curr. Diab. Rep.
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A new generation of genetic studies of diabetes is underway. Following from initial genome-wide association (GWA) studies, more recent approaches have used genotyping arrays of more densely spaced markers, imputation of ungenotyped variants based on improved reference haplotype panels, and sequencing of protein-coding exomes and whole genomes. Experimental and statistical advances make possible the identification of novel variants and loci contributing to trait variation and disease risk. Integration of sequence variants with functional analysis is critical to interpreting the consequences of identified variants. We briefly review these methods and technologies and describe how they will continue to expand our understanding of the genetic risk factors and underlying biology of diabetes.
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FTO genotype is associated with phenotypic variability of body mass index.
Jian Yang, Ruth J F Loos, Joseph E Powell, Sarah E Medland, Elizabeth K Speliotes, Daniel I Chasman, Lynda M Rose, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Reedik Mägi, Lindsay Waite, Albert Vernon Smith, Laura M Yerges-Armstrong, Keri L Monda, David Hadley, Anubha Mahajan, Guo Li, Karen Kapur, Veronique Vitart, Jennifer E Huffman, Sophie R Wang, Cameron Palmer, Tonu Esko, Krista Fischer, Jing Hua Zhao, Ayse Demirkan, Aaron Isaacs, Mary F Feitosa, Jian'an Luan, Nancy L Heard-Costa, Charles White, Anne U Jackson, Michael Preuss, Andreas Ziegler, Joel Eriksson, Zoltan Kutalik, Francesca Frau, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Jouke-Jan Hottenga, Kevin B Jacobs, Niek Verweij, Anuj Goel, Carolina Medina-Gomez, Karol Estrada, Jennifer Lynn Bragg-Gresham, Serena Sanna, Carlo Sidore, Jonathan Tyrer, Alexander Teumer, Inga Prokopenko, Massimo Mangino, Cecilia M Lindgren, Themistocles L Assimes, Alan R Shuldiner, Jennie Hui, John P Beilby, Wendy L McArdle, Per Hall, Talin Haritunians, Lina Zgaga, Ivana Kolčić, Ozren Polašek, Tatijana Zemunik, Ben A Oostra, M Juhani Junttila, Henrik Grönberg, Stefan Schreiber, Annette Peters, Andrew A Hicks, Jonathan Stephens, Nicola S Foad, Jaana Laitinen, Anneli Pouta, Marika Kaakinen, Gonneke Willemsen, Jacqueline M Vink, Sarah H Wild, Gerjan Navis, Folkert W Asselbergs, Georg Homuth, Ulrich John, Carlos Iribarren, Tamara Harris, Lenore Launer, Vilmundur Gudnason, Jeffrey R O'Connell, Eric Boerwinkle, Gemma Cadby, Lyle J Palmer, Alan L James, Arthur W Musk, Erik Ingelsson, Bruce M Psaty, Jacques S Beckmann, Gérard Waeber, Peter Vollenweider, Caroline Hayward, Alan F Wright, Igor Rudan, Leif C Groop, Andres Metspalu, Kay Tee Khaw, Cornelia M van Duijn, Ingrid B Borecki, Michael A Province, Nicholas J Wareham, Jean-Claude Tardif, Heikki V Huikuri, L Adrienne Cupples, Larry D Atwood, Caroline S Fox, Michael Boehnke, Francis S Collins, Karen L Mohlke, Jeanette Erdmann, Heribert Schunkert, Christian Hengstenberg, Klaus Stark, Mattias Lorentzon, Claes Ohlsson, Daniele Cusi, Jan A Staessen, Melanie M van der Klauw, Peter P Pramstaller, Sekar Kathiresan, Jennifer D Jolley, Samuli Ripatti, Marjo-Riitta Järvelin, Eco J C de Geus, Dorret I Boomsma, Brenda Penninx, James F Wilson, Harry Campbell, Stephen J Chanock, Pim van der Harst, Anders Hamsten, Hugh Watkins, Albert Hofman, Jacqueline C Witteman, M Carola Zillikens, André G Uitterlinden, Fernando Rivadeneira, Lambertus A Kiemeney, Sita H Vermeulen, Gonçalo R Abecasis, David Schlessinger, Sabine Schipf, Michael Stumvoll, Anke Tönjes, Tim D Spector, Kari E North, Guillaume Lettre, Mark I McCarthy, Sonja I Berndt, Andrew C Heath, Pamela A F Madden, Dale R Nyholt, Grant W Montgomery, Nicholas G Martin, Barbara McKnight, David P Strachan, William G Hill, Harold Snieder, Paul M Ridker, Unnur Thorsteinsdottir, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn, Michael E Goddard, Peter M Visscher.
Nature
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There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ?170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ?0.5?kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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Fine-mapping and initial characterization of QT interval loci in African Americans.
PLoS Genet.
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The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Womens Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P?1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P?1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
Robert A Scott, Vasiliki Lagou, Ryan P Welch, Eleanor Wheeler, May E Montasser, Jian'an Luan, Reedik Mägi, Rona J Strawbridge, Emil Rehnberg, Stefan Gustafsson, Stavroula Kanoni, Laura J Rasmussen-Torvik, Loïc Yengo, Cécile Lecoeur, Dmitry Shungin, Serena Sanna, Carlo Sidore, Paul C D Johnson, J Wouter Jukema, Toby Johnson, Anubha Mahajan, Niek Verweij, Gudmar Thorleifsson, Jouke-Jan Hottenga, Sonia Shah, Albert V Smith, Bengt Sennblad, Christian Gieger, Perttu Salo, Markus Perola, Nicholas J Timpson, David M Evans, Beate St Pourcain, Ying Wu, Jeanette S Andrews, Jennie Hui, Lawrence F Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron Isaacs, Jeffrey R O'Connell, Kathleen Stirrups, Veronique Vitart, Caroline Hayward, Tonu Esko, Evelin Mihailov, Ross M Fraser, Tove Fall, Benjamin F Voight, Soumya Raychaudhuri, Han Chen, Cecilia M Lindgren, Andrew P Morris, Nigel W Rayner, Neil Robertson, Denis Rybin, Ching-Ti Liu, Jacques S Beckmann, Sara M Willems, Peter S Chines, Anne U Jackson, Hyun Min Kang, Heather M Stringham, Kijoung Song, Toshiko Tanaka, John F Peden, Anuj Goel, Andrew A Hicks, Ping An, Martina Müller-Nurasyid, Anders Franco-Cereceda, Lasse Folkersen, Letizia Marullo, Hanneke Jansen, Albertine J Oldehinkel, Marcel Bruinenberg, James S Pankow, Kari E North, Nita G Forouhi, Ruth J F Loos, Sarah Edkins, Tibor V Varga, Göran Hallmans, Heikki Oksa, Mulas Antonella, Ramaiah Nagaraja, Stella Trompet, Ian Ford, Stephan J L Bakker, Augustine Kong, Meena Kumari, Bruna Gigante, Christian Herder, Patricia B Munroe, Mark Caulfield, Jula Antti, Massimo Mangino, Kerrin Small, Iva Miljkovic, Yongmei Liu, Mustafa Atalay, Wieland Kiess, Alan L James, Fernando Rivadeneira, André G Uitterlinden, Colin N A Palmer, Alex S F Doney, Gonneke Willemsen, Johannes H Smit, Susan Campbell, Ozren Polašek, Lori L Bonnycastle, Serge Hercberg, Maria Dimitriou, Jennifer L Bolton, Gerard R Fowkes, Peter Kovacs, Jaana Lindström, Tatijana Zemunik, Stefania Bandinelli, Sarah H Wild, Hanneke V Basart, Wolfgang Rathmann, Harald Grallert, , Winfried Maerz, Marcus E Kleber, Bernhard O Boehm, Annette Peters, Peter P Pramstaller, Michael A Province, Ingrid B Borecki, Nicholas D Hastie, Igor Rudan, Harry Campbell, Hugh Watkins, Martin Farrall, Michael Stumvoll, Luigi Ferrucci, Dawn M Waterworth, Richard N Bergman, Francis S Collins, Jaakko Tuomilehto, Richard M Watanabe, Eco J C de Geus, Brenda W Penninx, Albert Hofman, Ben A Oostra, Bruce M Psaty, Peter Vollenweider, James F Wilson, Alan F Wright, G Kees Hovingh, Andres Metspalu, Matti Uusitupa, Patrik K E Magnusson, Kirsten O Kyvik, Jaakko Kaprio, Jackie F Price, George V Dedoussis, Panos Deloukas, Pierre Meneton, Lars Lind, Michael Boehnke, Alan R Shuldiner, Cornelia M van Duijn, Andrew D Morris, Anke Toenjes, Patricia A Peyser, John P Beilby, Antje Körner, Johanna Kuusisto, Markku Laakso, Stefan R Bornstein, Peter E H Schwarz, Timo A Lakka, Rainer Rauramaa, Linda S Adair, George Davey Smith, Tim D Spector, Thomas Illig, Ulf de Faire, Anders Hamsten, Vilmundur Gudnason, Mika Kivimäki, Aroon Hingorani, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Dorret I Boomsma, Kari Stefansson, Pim van der Harst, Josée Dupuis, Nancy L Pedersen, Naveed Sattar, Tamara B Harris, Francesco Cucca, Samuli Ripatti, Veikko Salomaa, Karen L Mohlke, Beverley Balkau, Philippe Froguel, Anneli Pouta, Marjo-Riitta Järvelin, Nicholas J Wareham, Nabila Bouatia-Naji, Mark I McCarthy, Paul W Franks, James B Meigs, Tanya M Teslovich, Jose C Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso.
Nat. Genet.
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Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Andrew P Morris, Benjamin F Voight, Tanya M Teslovich, Teresa Ferreira, Ayellet V Segrè, Valgerdur Steinthorsdottir, Rona J Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tonu Esko, Ross M Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian'an Luan, Cecilia M Lindgren, Martina Müller-Nurasyid, Sonali Pechlivanis, N William Rayner, Laura J Scott, Steven Wiltshire, Loïc Yengo, Leena Kinnunen, Elizabeth J Rossin, Soumya Raychaudhuri, Andrew D Johnson, Antigone S Dimas, Ruth J F Loos, Sailaja Vedantam, Han Chen, Jose C Florez, Caroline Fox, Ching-Ti Liu, Denis Rybin, David J Couper, Wen Hong L Kao, Man Li, Marilyn C Cornelis, Peter Kraft, Qi Sun, Rob M Van Dam, Heather M Stringham, Peter S Chines, Krista Fischer, Pierre Fontanillas, Oddgeir L Holmen, Sarah E Hunt, Anne U Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R B Perry, Carl G P Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Gudmar Thorleifsson, Emmi Tikkanen, Andrew R Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L Bonnycastle, Noel Burtt, Jason Carey, Guillaume Charpentier, Andrew T Crenshaw, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsén, Karl Gertow, Bruna Gigante, George B Grant, Christopher J Groves, Candace Guiducci, Christian Herder, Astradur B Hreidarsson, Jennie Hui, Alan James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravic, Kaarel Krjutskov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu Mannisto, Ghazala Mirza, Thomas W Mühleisen, Bill Musk, Melissa Parkin, Loukianos Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigurðsson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia van Duijn, André G Uitterlinden, Albert Hofman, Eric Sijbrands, Gonçalo R Abecasis, Katharine R Owen, Eleftheria Zeggini, Mieke D Trip, Nita G Forouhi, Ann-Christine Syvänen, Johan G Eriksson, Leena Peltonen, Markus M Nöthen, Beverley Balkau, Colin N A Palmer, Valeriya Lyssenko, Tiinamaija Tuomi, Bo Isomaa, David J Hunter, Lu Qi, , Alan R Shuldiner, Michael Roden, Inês Barroso, Tom Wilsgaard, John Beilby, Kees Hovingh, Jackie F Price, James F Wilson, Rainer Rauramaa, Timo A Lakka, Lars Lind, George Dedoussis, Inger Njølstad, Nancy L Pedersen, Kay-Tee Khaw, Nicholas J Wareham, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Eeva Korpi-Hyövälti, Juha Saltevo, Markku Laakso, Johanna Kuusisto, Andres Metspalu, Francis S Collins, Karen L Mohlke, Richard N Bergman, Jaakko Tuomilehto, Bernhard O Boehm, Christian Gieger, Kristian Hveem, Stéphane Cauchi, Philippe Froguel, Damiano Baldassarre, Elena Tremoli, Steve E Humphries, Danish Saleheen, John Danesh, Erik Ingelsson, Samuli Ripatti, Veikko Salomaa, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Annette Peters, Thomas Illig, Ulf de Faire, Anders Hamsten, Andrew D Morris, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M Nilsson, Panos Deloukas, Unnur Thorsteinsdottir, Leif C Groop, Kari Stefansson, Frank Hu, James S Pankow, Josée Dupuis, James B Meigs, David Altshuler, Michael Boehnke, Mark I McCarthy.
Nat. Genet.
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To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
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Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
PLoS Genet.
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Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI?30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI?30 kg/m²), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P?=?8.4×10??, OR?=?1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P?=?0.04, OR?=?1.03 [95% CI 1.00-1.06]). A variant in HMG20A--previously identified in South Asians but not Europeans--was associated with type 2 diabetes in obese cases (P?=?1.3×10??, OR?=?1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P?=?0.02, OR?=?1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P?=?0.0002). In the lean analysis, we observed a weighted per-risk allele OR?=?1.13 [95% CI 1.10-1.17], P?=?3.2×10?¹?. This was larger than the same model fitted in the obese analysis where the OR?=?1.06 [95% CI 1.05-1.08], P?=?2.2×10?¹?. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
Benjamin F Voight, Gina M Peloso, Marju Orho-Melander, Ruth Frikke-Schmidt, Maja Barbalic, Majken K Jensen, George Hindy, Hilma Holm, Eric L Ding, Toby Johnson, Heribert Schunkert, Nilesh J Samani, Robert Clarke, Jemma C Hopewell, John F Thompson, Mingyao Li, Gudmar Thorleifsson, Christopher Newton-Cheh, Kiran Musunuru, James P Pirruccello, Danish Saleheen, Li Chen, Alexandre F R Stewart, Arne Schillert, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Sonia Anand, James C Engert, Thomas Morgan, John Spertus, Monika Stoll, Klaus Berger, Nicola Martinelli, Domenico Girelli, Pascal P McKeown, Christopher C Patterson, Stephen E Epstein, Joseph Devaney, Mary-Susan Burnett, Vincent Mooser, Samuli Ripatti, Ida Surakka, Markku S Nieminen, Juha Sinisalo, Marja-Liisa Lokki, Markus Perola, Aki Havulinna, Ulf de Faire, Bruna Gigante, Erik Ingelsson, Tanja Zeller, Philipp Wild, Paul I W de Bakker, Olaf H Klungel, Anke-Hilse Maitland-van der Zee, Bas J M Peters, Anthonius de Boer, Diederick E Grobbee, Pieter W Kamphuisen, Vera H M Deneer, Clara C Elbers, N Charlotte Onland-Moret, Marten H Hofker, Cisca Wijmenga, W M Monique Verschuren, Jolanda M A Boer, Yvonne T van der Schouw, Asif Rasheed, Philippe Frossard, Serkalem Demissie, Cristen Willer, Ron Do, José M Ordovás, Gonçalo R Abecasis, Michael Boehnke, Karen L Mohlke, Mark J Daly, Candace Guiducci, Noel P Burtt, Aarti Surti, Elena González, Shaun Purcell, Stacey Gabriel, Jaume Marrugat, John Peden, Jeanette Erdmann, Patrick Diemert, Christina Willenborg, Inke R König, Marcus Fischer, Christian Hengstenberg, Andreas Ziegler, Ian Buysschaert, Diether Lambrechts, Frans Van de Werf, Keith A Fox, Nour Eddine El Mokhtari, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber, Arne Schäfer, John Danesh, Stefan Blankenberg, Robert Roberts, Ruth McPherson, Hugh Watkins, Alistair S Hall, Kim Overvad, Eric Rimm, Eric Boerwinkle, Anne Tybjaerg-Hansen, L Adrienne Cupples, Muredach P Reilly, Olle Melander, Pier M Mannucci, Diego Ardissino, David Siscovick, Roberto Elosua, Kari Stefansson, Christopher J O'Donnell, Veikko Salomaa, Daniel J Rader, Leena Peltonen, Stephen M Schwartz, David Altshuler, Sekar Kathiresan.
Lancet
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High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
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A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.
Alisa K Manning, Marie-France Hivert, Robert A Scott, Jonna L Grimsby, Nabila Bouatia-Naji, Han Chen, Denis Rybin, Ching-Ti Liu, Lawrence F Bielak, Inga Prokopenko, Najaf Amin, Daniel Barnes, Gemma Cadby, Jouke-Jan Hottenga, Erik Ingelsson, Anne U Jackson, Toby Johnson, Stavroula Kanoni, Claes Ladenvall, Vasiliki Lagou, Jari Lahti, Cécile Lecoeur, Yongmei Liu, María Teresa Martínez-Larrad, May E Montasser, Pau Navarro, John R B Perry, Laura J Rasmussen-Torvik, Perttu Salo, Naveed Sattar, Dmitry Shungin, Rona J Strawbridge, Toshiko Tanaka, Cornelia M van Duijn, Ping An, Mariza de Andrade, Jeanette S Andrews, Thor Aspelund, Mustafa Atalay, Yurii Aulchenko, Beverley Balkau, Stefania Bandinelli, Jacques S Beckmann, John P Beilby, Claire Bellis, Richard N Bergman, John Blangero, Mladen Boban, Michael Boehnke, Eric Boerwinkle, Lori L Bonnycastle, Dorret I Boomsma, Ingrid B Borecki, Yvonne Böttcher, Claude Bouchard, Eric Brunner, Danijela Budimir, Harry Campbell, Olga Carlson, Peter S Chines, Robert Clarke, Francis S Collins, Arturo Corbatón-Anchuelo, David Couper, Ulf de Faire, George V Dedoussis, Panos Deloukas, Maria Dimitriou, Josephine M Egan, Gudny Eiriksdottir, Michael R Erdos, Johan G Eriksson, Elodie Eury, Luigi Ferrucci, Ian Ford, Nita G Forouhi, Caroline S Fox, Maria Grazia Franzosi, Paul W Franks, Timothy M Frayling, Philippe Froguel, Pilar Galán, Eco de Geus, Bruna Gigante, Nicole L Glazer, Anuj Goel, Leif Groop, Vilmundur Gudnason, Göran Hallmans, Anders Hamsten, Ola Hansson, Tamara B Harris, Caroline Hayward, Simon Heath, Serge Hercberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Jennie Hui, Joseph Hung, Marjo-Riitta Järvelin, Min A Jhun, Paul C D Johnson, J Wouter Jukema, Antti Jula, W H Kao, Jaakko Kaprio, Sharon L R Kardia, Sirkka Keinänen-Kiukaanniemi, Mika Kivimäki, Ivana Kolčić, Peter Kovacs, Meena Kumari, Johanna Kuusisto, Kirsten Ohm Kyvik, Markku Laakso, Timo Lakka, Lars Lannfelt, G Mark Lathrop, Lenore J Launer, Karin Leander, Guo Li, Lars Lind, Jaana Lindström, Stéphane Lobbens, Ruth J F Loos, Jian'an Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K E Magnusson, Michael Marmot, Pierre Meneton, Karen L Mohlke, Vincent Mooser, Mario A Morken, Iva Miljkovic, Narisu Narisu, Jeff O'Connell, Ken K Ong, Ben A Oostra, Lyle J Palmer, Aarno Palotie, James S Pankow, John F Peden, Nancy L Pedersen, Marina Pehlić, Leena Peltonen, Brenda Penninx, Marijana Pericic, Markus Perola, Louis Pérusse, Patricia A Peyser, Ozren Polašek, Peter P Pramstaller, Michael A Province, Katri Räikkönen, Rainer Rauramaa, Emil Rehnberg, Ken Rice, Jerome I Rotter, Igor Rudan, Aimo Ruokonen, Timo Saaristo, Maria Sabater-Lleal, Veikko Salomaa, David B Savage, Richa Saxena, Peter Schwarz, Udo Seedorf, Bengt Sennblad, Manuel Serrano-Ríos, Alan R Shuldiner, Eric J G Sijbrands, David S Siscovick, Johannes H Smit, Kerrin S Small, Nicholas L Smith, Albert Vernon Smith, Alena Stančáková, Kathleen Stirrups, Michael Stumvoll, Yan V Sun, Amy J Swift, Anke Tönjes, Jaakko Tuomilehto, Stella Trompet, André G Uitterlinden, Matti Uusitupa, Max Vikström, Veronique Vitart, Marie-Claude Vohl, Benjamin F Voight, Peter Vollenweider, Gérard Waeber, Dawn M Waterworth, Hugh Watkins, Eleanor Wheeler, Elisabeth Widén, Sarah H Wild, Sara M Willems, Gonneke Willemsen, James F Wilson, Jacqueline C M Witteman, Alan F Wright, Hanieh Yaghootkar, Diana Zelenika, Tatijana Zemunik, Lina Zgaga, , Nicholas J Wareham, Mark I McCarthy, Inês Barroso, Richard M Watanabe, Jose C Florez, Josée Dupuis, James B Meigs, Claudia Langenberg.
Nat. Genet.
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Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and ?-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
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Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.
PLoS ONE
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The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
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Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, , James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josée Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noel P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Paré, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Asa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena González, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-Der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, José M Ordovás, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan.
PLoS Genet.
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Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P?=?4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N?=?4,232 African Americans, N?=?1,776 Asians, and N?=?29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p?=?4.3×10(-3), n?=?22,044), increased triglycerides (p?=?2.6×10(-14), n?=?93,440), increased waist-to-hip ratio (p?=?1.8×10(-5), n?=?77,167), increased glucose two hours post oral glucose tolerance testing (p?=?4.4×10(-3), n?=?15,234), increased fasting insulin (p?=?0.015, n?=?48,238), but with lower in HDL-cholesterol concentrations (p?=?4.5×10(-13), n?=?96,748) and decreased BMI (p?=?1.4×10(-4), n?=?121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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Finding genes and variants for lipid levels after genome-wide association analysis.
Curr. Opin. Lipidol.
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We review the main findings from genome-wide association studies (GWAS) for levels of HDL-cholesterol, LDL-cholesterol and triglycerides, including approaches to identify the functional variant(s) or gene(s). We discuss study design and challenges related to whole genome or exome sequencing to identify novel genes and variants.
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A genome-wide association search for type 2 diabetes genes in African Americans.
Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, , Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michèle M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noel P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek.
PLoS ONE
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African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n?=?550 independent loci) were genotyped in a replication cohort and 122 SNPs (n?=?98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P?=?7.0×10(-9), OR (95% CI)?=?0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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