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Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-08-2014
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We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.
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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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Salt-inducible kinase 3, SIK3, is a new gene associated with hearing.
Hum. Mol. Genet.
PUBLISHED: 07-24-2014
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Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1-3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7×10(-8)) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.
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Is experimentally induced pain associated with socioeconomic status? Do poor people hurt more?
Med. Sci. Monit.
PUBLISHED: 07-18-2014
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The association of pain and socioeconomic status is widely reported, yet much less clearly understood. The aim of this study was to investigate the association of experimentally induced pain threshold and tolerance with socioeconomic status.
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Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
PLoS Genet.
PUBLISHED: 07-01-2014
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The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ?4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta?=?0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.
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Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.
PLoS Genet.
PUBLISHED: 07-01-2014
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Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding ?1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daniel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M Lahtinen, Ilja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Asa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D Kumar, Tamara B Harris, Lenore J Launer, Alan R Shuldiner, Alvaro Alonso, Joel S Bader, Georg Ehret, Hailiang Huang, W H Linda Kao, James B Strait, Peter W Macfarlane, Morris Brown, Mark J Caulfield, Nilesh J Samani, Florian Kronenberg, Johann Willeit, , J Gustav Smith, Karin H Greiser, Henriette Meyer zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R Heckbert, Bruce M Psaty, Jerome I Rotter, Ivana Kolčić, Ozren Polašek, Alan F Wright, Maura Griffin, Mark J Daly, David O Arnar, Hilma Holm, Unnur Thorsteinsdottir, Joshua C Denny, Dan M Roden, Rebecca L Zuvich, Valur Emilsson, Andrew S Plump, Martin G Larson, Christopher J O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P d'Adamo, AnnaMaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R Cummings, Michael A Nalls, Antti Jula, Kimmo K Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl-Heinz Jöckel, Hagen Kälsch, Markus M Nöthen, Marcel den Hoed, Ruth J F Loos, Dag S Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F Sinner, Melanie Waldenberger, Rudolf A de Boer, Lude Franke, Pieter A van der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A M Wilde, Elijah R Behr, Chrysoula Dalageorgou, John R Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M Hamilton, Stephen W Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E Moravec, Fabiola Del Greco M, Christian Fuchsberger, Jeffrey R O'Connell, Wai K Lee, Graham C M Watt, Harry Campbell, Sarah H Wild, Nour E El Mokhtari, Norbert Frey, Folkert W Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P van den Berg, Dirk J van Veldhuisen, Manolis Kellis, Bouwe P Krijthe, Oscar H Franco, Albert Hofman, Jan A Kors, André G Uitterlinden, Jacqueline C M Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A Oostra, Gonçalo R Abecasis, Edward G Lakatta, Antonella Mulas, Marco Orrù, David Schlessinger, Manuela Uda, Marcello R P Markus, Uwe Völker, Harold Snieder, Timothy D Spector, Johan Arnlöv, Lars Lind, Johan Sundström, Ann-Christine Syvänen, Mika Kivimäki, Mika Kähönen, Nina Mononen, Olli T Raitakari, Jorma S Viikari, Vera Adamkova, Stefan Kiechl, María Brión, Andrew N Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F Dominiczak, Fredrik Nyberg, Peter H Whincup, Aroon D Hingorani, Jean-Jacques Schott, Connie R Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F Wilson, Igor Rudan, Andre Franke, Thomas W Mühleisen, Peter P Pramstaller, Terho J Lehtimäki, Andrew D Paterson, Afshin Parsa, Yongmei Liu, Cornelia M van Duijn, David S Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B Felix, Serena Sanna, Marylyn D Ritchie, Bruno H Stricker, Kari Stefansson, Laurie A Boyer, Thomas P Cappola, Jesper V Olsen, Kasper Lage, Peter J Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J Ackerman, Arne Pfeufer, Paul I W de Bakker, Christopher Newton-Cheh.
Nat. Genet.
PUBLISHED: 05-29-2014
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The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ?8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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Genome-wide association analysis identifies six new loci associated with forced vital capacity.
Daan W Loth, María Soler Artigas, Sina A Gharib, Louise V Wain, Nora Franceschini, Beate Koch, Tess D Pottinger, Albert Vernon Smith, Qing Duan, Chris Oldmeadow, Mi Kyeong Lee, David P Strachan, Alan L James, Jennifer E Huffman, Veronique Vitart, Adaikalavan Ramasamy, Nicholas J Wareham, Jaakko Kaprio, Xin-Qun Wang, Holly Trochet, Mika Kähönen, Claudia Flexeder, Eva Albrecht, Lorna M Lopez, Kim de Jong, Bharat Thyagarajan, Alexessander Couto Alves, Stefan Enroth, Ernst Omenaas, Peter K Joshi, Tove Fall, Ana Viñuela, Lenore J Launer, Laura R Loehr, Myriam Fornage, Guo Li, Jemma B Wilk, Wenbo Tang, Ani Manichaikul, Lies Lahousse, Tamara B Harris, Kari E North, Alicja R Rudnicka, Jennie Hui, Xiangjun Gu, Thomas Lumley, Alan F Wright, Nicholas D Hastie, Susan Campbell, Rajesh Kumar, Isabelle Pin, Robert A Scott, Kirsi H Pietiläinen, Ida Surakka, Yongmei Liu, Elizabeth G Holliday, Holger Schulz, Joachim Heinrich, Gail Davies, Judith M Vonk, Mary Wojczynski, Anneli Pouta, Asa Johansson, Sarah H Wild, Erik Ingelsson, Fernando Rivadeneira, Henry Völzke, Pirro G Hysi, Gudny Eiriksdottir, Alanna C Morrison, Jerome I Rotter, Wei Gao, Dirkje S Postma, Wendy B White, Stephen S Rich, Albert Hofman, Thor Aspelund, David Couper, Lewis J Smith, Bruce M Psaty, Kurt Lohman, Esteban G Burchard, André G Uitterlinden, Melissa Garcia, Bonnie R Joubert, Wendy L McArdle, A Bill Musk, Nadia Hansel, Susan R Heckbert, Lina Zgaga, Joyce B J van Meurs, Pau Navarro, Igor Rudan, Yeon-Mok Oh, Susan Redline, Deborah L Jarvis, Jing Hua Zhao, Taina Rantanen, George T O'Connor, Samuli Ripatti, Rodney J Scott, Stefan Karrasch, Harald Grallert, Nathan C Gaddis, John M Starr, Cisca Wijmenga, Ryan L Minster, David J Lederer, Juha Pekkanen, Ulf Gyllensten, Harry Campbell, Andrew P Morris, Sven Gläser, Christopher J Hammond, Kristin M Burkart, John Beilby, Stephen B Kritchevsky, Vilmundur Gudnason, Dana B Hancock, O Dale Williams, Ozren Polašek, Tatijana Zemunik, Ivana Kolčić, Marcy F Petrini, Matthias Wjst, Woo Jin Kim, David J Porteous, Generation Scotland, Blair H Smith, Anne Viljanen, Markku Heliövaara, John R Attia, Ian Sayers, Regina Hampel, Christian Gieger, Ian J Deary, H Marike Boezen, Anne Newman, Marjo-Riitta Järvelin, James F Wilson, Lars Lind, Bruno H Stricker, Alexander Teumer, Timothy D Spector, Erik Melén, Marjolein J Peters, Leslie A Lange, R Graham Barr, Ken R Bracke, Fien M Verhamme, Joohon Sung, Pieter S Hiemstra, Patricia A Cassano, Akshay Sood, Caroline Hayward, Josée Dupuis, Ian P Hall, Guy G Brusselle, Martin D Tobin, Stephanie J London.
Nat. Genet.
PUBLISHED: 05-22-2014
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Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis.
Hum. Mol. Genet.
PUBLISHED: 04-15-2014
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To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.
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Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.
Hum. Genet.
PUBLISHED: 04-14-2014
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To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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Comparative performance of four methods for high-throughput glycosylation analysis of immunoglobulin G in genetic and epidemiological research.
Mol. Cell Proteomics
PUBLISHED: 04-09-2014
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The biological and clinical relevance of glycosylation is becoming increasingly recognized, leading to a growing interest in large-scale clinical and population-based studies. In the past few years, several methods for high-throughput analysis of glycans have been developed, but thorough validation and standardization of these methods is required before significant resources are invested in large-scale studies. In this study, we compared liquid chromatography, capillary gel electrophoresis, and two MS methods for quantitative profiling of N-glycosylation of IgG in the same data set of 1201 individuals. To evaluate the accuracy of the four methods we then performed analysis of association with genetic polymorphisms and age. Chromatographic methods with either fluorescent or MS-detection yielded slightly stronger associations than MS-only and multiplexed capillary gel electrophoresis, but at the expense of lower levels of throughput. Advantages and disadvantages of each method were identified, which should inform the selection of the most appropriate method in future studies.
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A general approach for haplotype phasing across the full spectrum of relatedness.
PLoS Genet.
PUBLISHED: 04-01-2014
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Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
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Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory.
Behav. Genet.
PUBLISHED: 03-20-2014
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Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
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Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.
Jie Huang, Jennifer E Huffman, Munekazu Yamakuchi, Munekazu Yamkauchi, Stella Trompet, Folkert W Asselbergs, Maria Sabater-Lleal, David-Alexandre Trégouët, Wei-Min Chen, Nicholas L Smith, Marcus E Kleber, So-Youn Shin, Diane M Becker, Weihong Tang, Abbas Dehghan, Andrew D Johnson, Vinh Truong, Lasse Folkersen, Qiong Yang, Tiphaine Oudot-Mellkah, Brendan M Buckley, Jason H Moore, Frances M K Williams, Harry Campbell, Günther Silbernagel, Veronique Vitart, Igor Rudan, Geoffrey H Tofler, Gerjan J Navis, Anita DeStefano, Alan F Wright, Ming-Huei Chen, Anton J M de Craen, Bradford B Worrall, Alicja R Rudnicka, Ann Rumley, Ebony B Bookman, Bruce M Psaty, Fang Chen, Keith L Keene, Oscar H Franco, Bernhard O Böhm, André G Uitterlinden, Angela M Carter, J Wouter Jukema, Naveed Sattar, Joshua C Bis, Mohammad A Ikram, , Michèle M Sale, Barbara McKnight, Myriam Fornage, Ian Ford, Kent Taylor, P Eline Slagboom, Wendy L McArdle, Fang-Chi Hsu, Anders Franco-Cereceda, Alison H Goodall, Lisa R Yanek, Karen L Furie, Mary Cushman, Albert Hofman, Jacqueline C M Witteman, Aaron R Folsom, Saonli Basu, Nena Matijevic, Wiek H van Gilst, James F Wilson, Rudi G J Westendorp, Sekar Kathiresan, Muredach P Reilly, Russell P Tracy, Ozren Polašek, Bernhard R Winkelmann, Peter J Grant, Hans L Hillege, Francois Cambien, David J Stott, Gordon D Lowe, Timothy D Spector, James B Meigs, Winfried März, Per Eriksson, Lewis C Becker, Pierre-Emmanuel Morange, Nicole Soranzo, Scott M Williams, Caroline Hayward, Pim van der Harst, Anders Hamsten, Charles J Lowenstein, David P Strachan, Christopher J O'Donnell.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 02-27-2014
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Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.
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Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.
J. Am. Soc. Nephrol.
PUBLISHED: 02-27-2014
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Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 ?g/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.
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Common genetic variants explain the majority of the correlation between height and intelligence: the generation Scotland study.
Behav. Genet.
PUBLISHED: 01-29-2014
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Greater height and higher intelligence test scores are predictors of better health outcomes. Here, we used molecular (single-nucleotide polymorphism) data to estimate the genetic correlation between height and general intelligence (g) in 6,815 unrelated subjects (median age 57, IQR 49-63) from the Generation Scotland: Scottish Family Health Study cohort. The phenotypic correlation between height and g was 0.16 (SE 0.01). The genetic correlation between height and g was 0.28 (SE 0.09) with a bivariate heritability estimate of 0.71. Understanding the molecular basis of the correlation between height and intelligence may help explain any shared role in determining health outcomes. This study identified a modest genetic correlation between height and intelligence with the majority of the phenotypic correlation being explained by shared genetic influences.
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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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Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.
Leslie A Lange, Youna Hu, He Zhang, Chenyi Xue, Ellen M Schmidt, Zheng-zheng Tang, Chris Bizon, Ethan M Lange, Joshua D Smith, Emily H Turner, Goo Jun, Hyun Min Kang, Gina Peloso, Paul Auer, Kuo-Ping Li, Jason Flannick, Ji Zhang, Christian Fuchsberger, Kyle Gaulton, Cecilia Lindgren, Adam Locke, Alisa Manning, Xueling Sim, Manuel A Rivas, Oddgeir L Holmen, Omri Gottesman, Yingchang Lu, Douglas Ruderfer, Eli A Stahl, Qing Duan, Yun Li, Peter Durda, Shuo Jiao, Aaron Isaacs, Albert Hofman, Joshua C Bis, Adolfo Correa, Michael E Griswold, Johanna Jakobsdottir, Albert V Smith, Pamela J Schreiner, Mary F Feitosa, Qunyuan Zhang, Jennifer E Huffman, Jacy Crosby, Christina L Wassel, Ron Do, Nora Franceschini, Lisa W Martin, Jennifer G Robinson, Themistocles L Assimes, David R Crosslin, Elisabeth A Rosenthal, Michael Tsai, Mark J Rieder, Deborah N Farlow, Aaron R Folsom, Thomas Lumley, Ervin R Fox, Christopher S Carlson, Ulrike Peters, Rebecca D Jackson, Cornelia M van Duijn, André G Uitterlinden, Daniel Levy, Jerome I Rotter, Herman A Taylor, Vilmundur Gudnason, David S Siscovick, Myriam Fornage, Ingrid B Borecki, Caroline Hayward, Igor Rudan, Y Eugene Chen, Erwin P Bottinger, Ruth J F Loos, Pål Sætrom, Kristian Hveem, Michael Boehnke, Leif Groop, Mark McCarthy, Thomas Meitinger, Christie M Ballantyne, Stacey B Gabriel, Christopher J O'Donnell, Wendy S Post, Kari E North, Alexander P Reiner, Eric Boerwinkle, Bruce M Psaty, David Altshuler, Sekar Kathiresan, Dan-Yu Lin, Gail P Jarvik, L Adrienne Cupples, Charles Kooperberg, James G Wilson, Deborah A Nickerson, Gonçalo R Abecasis, Stephen S Rich, Russell P Tracy, Cristen J Willer, .
Am. J. Hum. Genet.
PUBLISHED: 01-14-2014
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Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
Alireza Moayyeri, Yi-Hsiang Hsu, David Karasik, Karol Estrada, Su-Mei Xiao, Carrie Nielson, Priya Srikanth, Sylvie Giroux, Scott G Wilson, Hou-Feng Zheng, Albert V Smith, Stephen R Pye, Paul J Leo, Alexander Teumer, Joo-Yeon Hwang, Claes Ohlsson, Fiona McGuigan, Ryan L Minster, Caroline Hayward, José M Olmos, Leo-Pekka Lyytikäinen, Joshua R Lewis, Karin M A Swart, Laura Masi, Chris Oldmeadow, Elizabeth G Holliday, Sulin Cheng, Natasja M van Schoor, Nicholas C Harvey, Marcin Kruk, Fabiola Del Greco M, Wilmar Igl, Olivia Trummer, Efi Grigoriou, Robert Luben, Ching-Ti Liu, Yanhua Zhou, Ling Oei, Carolina Medina-Gomez, Joseph Zmuda, Greg Tranah, Suzanne J Brown, Frances M Williams, Nicole Soranzo, Johanna Jakobsdottir, Kristin Siggeirsdottir, Kate L Holliday, Anke Hannemann, Min Jin Go, Melissa Garcia, Ozren Polašek, Marika Laaksonen, Kun Zhu, Anke W Enneman, Mark McEvoy, Roseanne Peel, Pak Chung Sham, Maciej Jaworski, Asa Johansson, Andrew A Hicks, Pawel Pludowski, Rodney Scott, Rosalie A M Dhonukshe-Rutten, Nathalie van der Velde, Mika Kähönen, Jorma S Viikari, Harri Sievänen, Olli T Raitakari, Jesús González-Macías, José L Hernández, Dan Mellström, Osten Ljunggren, Yoon Shin Cho, Uwe Völker, Matthias Nauck, Georg Homuth, Henry Völzke, Robin Haring, Matthew A Brown, Eugene McCloskey, Geoffrey C Nicholson, Richard Eastell, John A Eisman, Graeme Jones, Ian R Reid, Elaine M Dennison, John Wark, Steven Boonen, Dirk Vanderschueren, Frederick C W Wu, Thor Aspelund, J Brent Richards, Doug Bauer, Albert Hofman, Kay-Tee Khaw, George Dedoussis, Barbara Obermayer-Pietsch, Ulf Gyllensten, Peter P Pramstaller, Roman S Lorenc, Cyrus Cooper, Annie Wai Chee Kung, Paul Lips, Markku Alen, John Attia, Maria Luisa Brandi, Lisette C P G M de Groot, Terho Lehtimäki, José A Riancho, Harry Campbell, Yongmei Liu, Tamara B Harris, Kristina Akesson, Magnus Karlsson, Jong-Young Lee, Henri Wallaschofski, Emma L Duncan, Terence W O'Neill, Vilmundur Gudnason, Timothy D Spector, François Rousseau, Eric Orwoll, Steven R Cummings, Nick J Wareham, Fernando Rivadeneira, André G Uitterlinden, Richard L Prince, Douglas P Kiel, Jonathan Reeve, Stephen K Kaptoge.
Hum. Mol. Genet.
PUBLISHED: 01-14-2014
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Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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Molecular genetic contributions to socioeconomic status and intelligence.
Intelligence
PUBLISHED: 01-10-2014
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Education, socioeconomic status, and intelligence are commonly used as predictors of health outcomes, social environment, and mortality. Education and socioeconomic status are typically viewed as environmental variables although both correlate with intelligence, which has a substantial genetic basis. Using data from 6815 unrelated subjects from the Generation Scotland study, we examined the genetic contributions to these variables and their genetic correlations. Subjects underwent genome-wide testing for common single nucleotide polymorphisms (SNPs). DNA-derived heritability estimates and genetic correlations were calculated using the 'Genome-wide Complex Trait Analyses' (GCTA) procedures. 21% of the variation in education, 18% of the variation in socioeconomic status, and 29% of the variation in general cognitive ability was explained by variation in common SNPs (SEs ~ 5%). The SNP-based genetic correlations of education and socioeconomic status with general intelligence were 0.95 (SE 0.13) and 0.26 (0.16), respectively. There are genetic contributions to intelligence and education with near-complete overlap between common additive SNP effects on these traits (genetic correlation ~ 1). Genetic influences on socioeconomic status are also associated with the genetic foundations of intelligence. The results are also compatible with substantial environmental contributions to socioeconomic status.
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Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
Gina M Peloso, Paul L Auer, Joshua C Bis, Arend Voorman, Alanna C Morrison, Nathan O Stitziel, Jennifer A Brody, Sumeet A Khetarpal, Jacy R Crosby, Myriam Fornage, Aaron Isaacs, Johanna Jakobsdottir, Mary F Feitosa, Gail Davies, Jennifer E Huffman, Ani Manichaikul, Brian Davis, Kurt Lohman, Aron Y Joon, Albert V Smith, Megan L Grove, Paolo Zanoni, Valeska Redon, Serkalem Demissie, Kim Lawson, Ulrike Peters, Christopher Carlson, Rebecca D Jackson, Kelli K Ryckman, Rachel H Mackey, Jennifer G Robinson, David S Siscovick, Pamela J Schreiner, Josyf C Mychaleckyj, James S Pankow, Albert Hofman, André G Uitterlinden, Tamara B Harris, Kent D Taylor, Jeanette M Stafford, Lindsay M Reynolds, Riccardo E Marioni, Abbas Dehghan, Oscar H Franco, Aniruddh P Patel, Yingchang Lu, George Hindy, Omri Gottesman, Erwin P Bottinger, Olle Melander, Marju Orho-Melander, Ruth J F Loos, Stefano Duga, Piera Angelica Merlini, Martin Farrall, Anuj Goel, Rosanna Asselta, Domenico Girelli, Nicola Martinelli, Svati H Shah, William E Kraus, Mingyao Li, Daniel J Rader, Muredach P Reilly, Ruth McPherson, Hugh Watkins, Diego Ardissino, , Qunyuan Zhang, Judy Wang, Michael Y Tsai, Herman A Taylor, Adolfo Correa, Michael E Griswold, Leslie A Lange, John M Starr, Igor Rudan, Gudny Eiriksdottir, Lenore J Launer, José M Ordovás, Daniel Levy, Y-D Ida Chen, Alexander P Reiner, Caroline Hayward, Ozren Polašek, Ian J Deary, Ingrid B Borecki, Yongmei Liu, Vilmundur Gudnason, James G Wilson, Cornelia M van Duijn, Charles Kooperberg, Stephen S Rich, Bruce M Psaty, Jerome I Rotter, Christopher J O'Donnell, Kenneth Rice, Eric Boerwinkle, Sekar Kathiresan, L Adrienne Cupples.
Am. J. Hum. Genet.
PUBLISHED: 01-09-2014
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Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
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Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.
PLoS ONE
PUBLISHED: 01-01-2014
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Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p?=?1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value?=?9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
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The total burden of rare, non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability.
Proc. Biol. Sci.
PUBLISHED: 01-01-2014
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Human cognitive ability shows consistent, positive associations with fitness components across the life-course. Underlying genetic variation should therefore be depleted by selection, which is not observed. Genetic variation in general cognitive ability (intelligence) could be maintained by a mutation-selection balance, with rare variants contributing to its genetic architecture. This study examines the association between the total number of rare stop-gain/loss, splice and missense exonic variants and cognitive ability in childhood and old age in the same individuals. Exome array data were obtained in the Lothian Birth Cohorts of 1921 and 1936 (combined N = 1596). General cognitive ability was assessed at age 11 years and in late life (79 and 70 years, respectively) and was modelled against the total number of stop-gain/loss, splice, and missense exonic variants, with minor allele frequency less than or equal to 0.01, using linear regression adjusted for age and sex. In both cohorts and in both the childhood and late-life models, there were no significant associations between rare variant burden in the exome and cognitive ability that survived correction for multiple testing. Contrary to our a priori hypothesis, we observed no evidence for an association between the total number of rare exonic variants and either childhood cognitive ability or late-life cognitive ability.
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DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.
Hum. Mol. Genet.
PUBLISHED: 12-19-2013
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Length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to about 50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits, to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using Genome-wide Complex Trait Analysis (GCTA). However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P=1.9x10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
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Glycans Are a Novel Biomarker of Chronological and Biological Ages.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 12-10-2013
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Fine structural details of glycans attached to the conserved N-glycosylation site significantly not only affect function of individual immunoglobulin G (IgG) molecules but also mediate inflammation at the systemic level. By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age. Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these three glycans can explain up to 58% of variance in chronological age, significantly more than other markers of biological age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age. Thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. Considering the important role of IgG glycans in inflammation, and because the observed changes with age promote inflammation, changes in IgG glycosylation also seem to represent a factor contributing to aging.Significance StatementGlycosylation is the key posttranslational mechanism that regulates function of immunoglobulins, with multiple systemic repercussions to the immune system. Our study of IgG glycosylation in 5,117 individuals from four European populations has revealed very extensive and complex changes in IgG glycosylation with age. The combined index composed of only three glycans explained up to 58% of variance in age, considerably more than other biomarkers of age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age; thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. The ability to measure human biological aging using molecular profiling has practical applications for diverse fields such as disease prevention and treatment, or forensics.
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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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Common variants in mendelian kidney disease genes and their association with renal function.
Afshin Parsa, Christian Fuchsberger, Anna Köttgen, Conall M O'Seaghdha, Cristian Pattaro, Mariza de Andrade, Daniel I Chasman, Alexander Teumer, Karlhans Endlich, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Young J Kim, Daniel Taliun, Man Li, Mary Feitosa, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Nicole Glazer, Aaron Isaacs, Madhumathi Rao, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Asa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Couraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tonu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Edith Hofer, Frank Hu, Ayse Demirkan, Ben A Oostra, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Franco Giulianini, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Lina Zgaga, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, André G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polašek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Bénédicte Stengel, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Helen Colhoun, Alex Doney, Antonietta Robino, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Paul Mitchell, Marina Ciullo, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline Witteman, Caroline Hayward, Paul M Ridker, Murielle Bochud, Iris M Heid, David S Siscovick, Caroline S Fox, W Linda Kao, Carsten A Böger.
J. Am. Soc. Nephrol.
PUBLISHED: 09-12-2013
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Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.
Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltan Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Macé, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolčić, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio D'adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, André G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, , Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polašek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, Murielle Bochud.
PLoS Genet.
PUBLISHED: 09-01-2013
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Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ? 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
Maria Sabater-Lleal, Jie Huang, Daniel Chasman, Silvia Naitza, Abbas Dehghan, Andrew D Johnson, Alexander Teumer, Alex P Reiner, Lasse Folkersen, Saonli Basu, Alicja R Rudnicka, Stella Trompet, Anders Malarstig, Jens Baumert, Joshua C Bis, Xiuqing Guo, Jouke J Hottenga, So-Youn Shin, Lorna M Lopez, Jari Lahti, Toshiko Tanaka, Lisa R Yanek, Tiphaine Oudot-Mellakh, James F Wilson, Pau Navarro, Jennifer E Huffman, Tatijana Zemunik, Susan Redline, Reena Mehra, Drazen Pulanić, Igor Rudan, Alan F Wright, Ivana Kolčić, Ozren Polašek, Sarah H Wild, Harry Campbell, J David Curb, Robert Wallace, Simin Liu, Charles B Eaton, Diane M Becker, Lewis C Becker, Stefania Bandinelli, Katri Räikkönen, Elisabeth Widén, Aarno Palotie, Myriam Fornage, David Green, Myron Gross, Gail Davies, Sarah E Harris, David C Liewald, John M Starr, Frances M K Williams, Peter J Grant, Timothy D Spector, Rona J Strawbridge, Angela Silveira, Bengt Sennblad, Fernando Rivadeneira, André G Uitterlinden, Oscar H Franco, Albert Hofman, Jenny van Dongen, Gonneke Willemsen, Dorret I Boomsma, Jie Yao, Nancy Swords Jenny, Talin Haritunians, Barbara McKnight, Thomas Lumley, Kent D Taylor, Jerome I Rotter, Bruce M Psaty, Annette Peters, Christian Gieger, Thomas Illig, Anne Grotevendt, Georg Homuth, Henry Völzke, Thomas Kocher, Anuj Goel, Maria Grazia Franzosi, Udo Seedorf, Robert Clarke, Maristella Steri, Kirill V Tarasov, Serena Sanna, David Schlessinger, David J Stott, Naveed Sattar, Brendan M Buckley, Ann Rumley, Gordon D Lowe, Wendy L McArdle, Ming-Huei Chen, Geoffrey H Tofler, Jaejoon Song, Eric Boerwinkle, Aaron R Folsom, Lynda M Rose, Anders Franco-Cereceda, Martina Teichert, M Arfan Ikram, Thomas H Mosley, Steve Bevan, Martin Dichgans, Peter M Rothwell, Cathie L M Sudlow, Jemma C Hopewell, John C Chambers, Danish Saleheen, Jaspal S Kooner, John Danesh, Christopher P Nelson, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Pierre-Emmanuel Morange, Luigi Ferrucci, Johan G Eriksson, David Jacobs, Ian J Deary, Nicole Soranzo, Jacqueline C M Witteman, Eco J C de Geus, Russell P Tracy, Caroline Hayward, Wolfgang Koenig, Francesco Cucca, J Wouter Jukema, Per Eriksson, Sudha Seshadri, Hugh S Markus, Hugh Watkins, Nilesh J Samani, , Henri Wallaschofski, Nicholas L Smith, David Tregouet, Paul M Ridker, Weihong Tang, David P Strachan, Anders Hamsten, Christopher J O'Donnell.
Circulation
PUBLISHED: 08-22-2013
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Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.
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Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.
PLoS Genet.
PUBLISHED: 08-01-2013
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Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of ? = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.
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The association between galactosylation of immunoglobulin G and body mass index.
Prog. Neuropsychopharmacol. Biol. Psychiatry
PUBLISHED: 07-27-2013
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Obesity is becoming a fast-growing health problem worldwide. Glycosylation of proteins and their variations significantly affect protein structure and function, thus altering numerous physiological and pathophysiological cellular processes. Since plasma glycans were significantly associated with body mass index (BMI) in both Croatian and Chinese populations, the study evaluated the association between immunoglobulin G (IgG) glycome, which is closer to biological function, and BMI.
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Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.
Hum. Mol. Genet.
PUBLISHED: 07-19-2013
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It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.
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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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GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.
Cornelius A Rietveld, Sarah E Medland, Jaime Derringer, Jian Yang, Tonu Esko, Nicolas W Martin, Harm-Jan Westra, Konstantin Shakhbazov, Abdel Abdellaoui, Arpana Agrawal, Eva Albrecht, Behrooz Z Alizadeh, Najaf Amin, John Barnard, Sebastian E Baumeister, Kelly S Benke, Lawrence F Bielak, Jeffrey A Boatman, Patricia A Boyle, Gail Davies, Christiaan de Leeuw, Niina Eklund, Daniel S Evans, Rudolf Ferhmann, Krista Fischer, Christian Gieger, Håkon K Gjessing, Sara Hägg, Jennifer R Harris, Caroline Hayward, Christina Holzapfel, Carla A Ibrahim-Verbaas, Erik Ingelsson, Bo Jacobsson, Peter K Joshi, Astanand Jugessur, Marika Kaakinen, Stavroula Kanoni, Juha Karjalainen, Ivana Kolčić, Kati Kristiansson, Zoltan Kutalik, Jari Lahti, Sang H Lee, Peng Lin, Penelope A Lind, Yongmei Liu, Kurt Lohman, Marisa Loitfelder, George McMahon, Pedro Marques Vidal, Osorio Meirelles, Lili Milani, Ronny Myhre, Marja-Liisa Nuotio, Christopher J Oldmeadow, Katja E Petrovic, Wouter J Peyrot, Ozren Polašek, Lydia Quaye, Eva Reinmaa, John P Rice, Thais S Rizzi, Helena Schmidt, Reinhold Schmidt, Albert V Smith, Jennifer A Smith, Toshiko Tanaka, Antonio Terracciano, Matthijs J H M van der Loos, Veronique Vitart, Henry Völzke, Jürgen Wellmann, Lei Yu, Wei Zhao, Jüri Allik, John R Attia, Stefania Bandinelli, François Bastardot, Jonathan Beauchamp, David A Bennett, Klaus Berger, Laura J Bierut, Dorret I Boomsma, Ute Bültmann, Harry Campbell, Christopher F Chabris, Lynn Cherkas, Mina K Chung, Francesco Cucca, Mariza de Andrade, Philip L De Jager, Jan-Emmanuel De Neve, Ian J Deary, George V Dedoussis, Panos Deloukas, Maria Dimitriou, Guðný Eiríksdóttir, Martin F Elderson, Johan G Eriksson, David M Evans, Jessica D Faul, Luigi Ferrucci, Melissa E Garcia, Henrik Grönberg, Vilmundur Guðnason, Per Hall, Juliette M Harris, Tamara B Harris, Nicholas D Hastie, Andrew C Heath, Dena G Hernandez, Wolfgang Hoffmann, Adriaan Hofman, Rolf Holle, Elizabeth G Holliday, Jouke-Jan Hottenga, William G Iacono, Thomas Illig, Marjo-Riitta Järvelin, Mika Kähönen, Jaakko Kaprio, Robert M Kirkpatrick, Matthew Kowgier, Antti Latvala, Lenore J Launer, Debbie A Lawlor, Terho Lehtimäki, Jingmei Li, Paul Lichtenstein, Peter Lichtner, David C Liewald, Pamela A Madden, Patrik K E Magnusson, Tomi E Mäkinen, Marco Masala, Matt McGue, Andres Metspalu, Andreas Mielck, Michael B Miller, Grant W Montgomery, Sutapa Mukherjee, Dale R Nyholt, Ben A Oostra, Lyle J Palmer, Aarno Palotie, Brenda W J H Penninx, Markus Perola, Patricia A Peyser, Martin Preisig, Katri Räikkönen, Olli T Raitakari, Anu Realo, Susan M Ring, Samuli Ripatti, Fernando Rivadeneira, Igor Rudan, Aldo Rustichini, Veikko Salomaa, Antti-Pekka Sarin, David Schlessinger, Rodney J Scott, Harold Snieder, Beate St Pourcain, John M Starr, Jae Hoon Sul, Ida Surakka, Rauli Svento, Alexander Teumer, , Henning Tiemeier, Frank J A van Rooij, David R Van Wagoner, Erkki Vartiainen, Jorma Viikari, Peter Vollenweider, Judith M Vonk, Gérard Waeber, David R Weir, H-Erich Wichmann, Elisabeth Widén, Gonneke Willemsen, James F Wilson, Alan F Wright, Dalton Conley, George Davey-Smith, Lude Franke, Patrick J F Groenen, Albert Hofman, Magnus Johannesson, Sharon L R Kardia, Robert F Krueger, David Laibson, Nicholas G Martin, Michelle N Meyer, Danielle Posthuma, A Roy Thurik, Nicholas J Timpson, André G Uitterlinden, Cornelia M van Duijn, Peter M Visscher, Daniel J Benjamin, David Cesarini, Philipp D Koellinger.
Science
PUBLISHED: 05-30-2013
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A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ? 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ?2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
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Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment.
Hum. Mol. Genet.
PUBLISHED: 04-11-2013
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Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.
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Association of adiposity genetic variants with menarche timing in 92,105 women of European descent.
Am. J. Epidemiol.
PUBLISHED: 04-04-2013
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Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
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Can genetics aggravate the health of isolated and remote populations? The case of gout, hyperuricaemia and osteoarthritis in Dalmatia.
Rural Remote Health
PUBLISHED: 03-26-2013
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The aim of this study was to investigate whether genetics may be considered an additional risk factor for health in isolated and remote populations, compared with their populations of origin. In this study, two remote island population samples from Croatia (from the islands of Vis and the Korcula) were compared with mainland controls from the coastal city of Split. The analyses focused on gout, hyperuricaemia and osteoarthritis, as examples of complex, multifactorial diseases.
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, Bianca J J M Brundel, David S Peal, David M Evans, Ilja M Nolte, Ayellet V Segrè, Hilma Holm, Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle Bochud, Gabrielle Boucher, Marilyn C Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U Jackson, Zoltan Kutalik, Jian'an Luan, John P Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E Montasser, Omer T Njajou, Paul F O'Reilly, Sandosh Padmanabhan, Beate St Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H M Draisma, Mary F Feitosa, Kathleen F Kerr, Penelope A Lind, Evelin Mihailov, N Charlotte Onland-Moret, Ci Song, Michael N Weedon, Weijia Xie, Loïc Yengo, Devin Absher, Christine M Albert, Alvaro Alonso, Dan E Arking, Paul I W de Bakker, Beverley Balkau, Cristina Barlassina, Paola Benaglio, Joshua C Bis, Nabila Bouatia-Naji, Søren Brage, Stephen J Chanock, Peter S Chines, Mina Chung, Dawood Darbar, Christian Dina, Marcus Dörr, Paul Elliott, Stephan B Felix, Krista Fischer, Christian Fuchsberger, Eco J C de Geus, Philippe Goyette, Vilmundur Gudnason, Tamara B Harris, Anna-Liisa Hartikainen, Aki S Havulinna, Susan R Heckbert, Andrew A Hicks, Albert Hofman, Suzanne Holewijn, Femke Hoogstra-Berends, Jouke-Jan Hottenga, Majken K Jensen, Asa Johansson, Juhani Junttila, Stefan Kääb, Bart Kanon, Shamika Ketkar, Kay-Tee Khaw, Joshua W Knowles, Angrad S Kooner, Jan A Kors, Meena Kumari, Lili Milani, Päivi Laiho, Edward G Lakatta, Claudia Langenberg, Maarten Leusink, Yongmei Liu, Robert N Luben, Kathryn L Lunetta, Stacey N Lynch, Marcello R P Markus, Pedro Marques-Vidal, Irene Mateo Leach, Wendy L McArdle, Steven A McCarroll, Sarah E Medland, Kathryn A Miller, Grant W Montgomery, Alanna C Morrison, Martina Müller-Nurasyid, Pau Navarro, Mari Nelis, Jeffrey R O'Connell, Christopher J O'Donnell, Ken K Ong, Anne B Newman, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Bruce M Psaty, Dabeeru C Rao, Susan M Ring, Elizabeth J Rossin, Diana Rudan, Serena Sanna, Robert A Scott, Jaban S Sehmi, Stephen Sharp, Jordan T Shin, Andrew B Singleton, Albert V Smith, Nicole Soranzo, Tim D Spector, Chip Stewart, Heather M Stringham, Kirill V Tarasov, André G Uitterlinden, Liesbeth Vandenput, Shih-Jen Hwang, John B Whitfield, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, James F Wilson, Jacqueline C M Witteman, Andrew Wong, Quenna Wong, Yalda Jamshidi, Paavo Zitting, Jolanda M A Boer, Dorret I Boomsma, Ingrid B Borecki, Cornelia M van Duijn, Ulf Ekelund, Nita G Forouhi, Philippe Froguel, Aroon Hingorani, Erik Ingelsson, Mika Kivimäki, Richard A Kronmal, Diana Kuh, Lars Lind, Nicholas G Martin, Ben A Oostra, Nancy L Pedersen, Thomas Quertermous, Jerome I Rotter, Yvonne T van der Schouw, W M Monique Verschuren, Mark Walker, Demetrius Albanes, David O Arnar, Themistocles L Assimes, Stefania Bandinelli, Michael Boehnke, Rudolf A de Boer, Claude Bouchard, W L Mark Caulfield, John C Chambers, Gary Curhan, Daniele Cusi, Johan Eriksson, Luigi Ferrucci, Wiek H van Gilst, Nicola Glorioso, Jacqueline de Graaf, Leif Groop, Ulf Gyllensten, Wen-Chi Hsueh, Frank B Hu, Heikki V Huikuri, David J Hunter, Carlos Iribarren, Bo Isomaa, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Lambertus A Kiemeney, Melanie M van der Klauw, Jaspal S Kooner, Peter Kraft, Licia Iacoviello, Terho Lehtimäki, Marja-Liisa L Lokki, Braxton D Mitchell, Gerjan Navis, Markku S Nieminen, Claes Ohlsson, Neil R Poulter, Lu Qi, Olli T Raitakari, Eric B Rimm, John D Rioux, Federica Rizzi, Igor Rudan, Veikko Salomaa, Peter S Sever, Denis C Shields, Alan R Shuldiner, Juha Sinisalo, Alice V Stanton, Ronald P Stolk, David P Strachan, Jean-Claude Tardif, Unnur Thorsteinsdottir, Jaako Tuomilehto, Dirk J van Veldhuisen, Jarmo Virtamo, Jorma Viikari, Peter Vollenweider, Gérard Waeber, Elisabeth Widén, Yoon Shin Cho, Jesper V Olsen, Peter M Visscher, Cristen Willer, Lude Franke, , Jeanette Erdmann, John R Thompson, Arne Pfeufer, Nona Sotoodehnia, Christopher Newton-Cheh, Patrick T Ellinor, Bruno H Ch Stricker, Andres Metspalu, Markus Perola, Jacques S Beckmann, George Davey Smith, Kari Stefansson, Nicholas J Wareham, Patricia B Munroe, Ody C M Sibon, David J Milan, Harold Snieder, Nilesh J Samani, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 03-21-2013
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Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
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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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Pedigree and genotyping quality analyses of over 10,000 DNA samples from the Generation Scotland: Scottish Family Health Study.
BMC Med. Genet.
PUBLISHED: 03-14-2013
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Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity.
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Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.
Hum. Mol. Genet.
PUBLISHED: 03-07-2013
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Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (Cooperative Health Research in the Region of Augsburg); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
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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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Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.
PLoS Genet.
PUBLISHED: 01-31-2013
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Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27 × 10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohns disease, diabetes type 1, multiple sclerosis, Graves disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.
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Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.
Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart MacGregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, Ekaterina Yonova-Doing, Xin Zhou, M Kamran Ikram, Gabriëlle H S Buitendijk, George McMahon, John P Kemp, Beate St Pourcain, Claire L Simpson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Andrew D Paterson, S Mohsen Hosseini, Hoi Suen Wong, Liang Xu, Jost B Jonas, Olavi Pärssinen, Juho Wedenoja, Shea Ping Yip, Daniel W H Ho, Chi Pui Pang, Li Jia Chen, Kathryn P Burdon, Jamie E Craig, Barbara E K Klein, Ronald Klein, Toomas Haller, Andres Metspalu, Chiea-Chuen Khor, E-Shyong Tai, Tin Aung, Eranga Vithana, Wan-Ting Tay, Veluchamy A Barathi, , Peng Chen, Ruoying Li, Jiemin Liao, Yingfeng Zheng, Rick T Ong, Angela Döring, David M Evans, Nicholas J Timpson, Annemieke J M H Verkerk, Thomas Meitinger, Olli Raitakari, Felicia Hawthorne, Tim D Spector, Lennart C Karssen, Mario Pirastu, Federico Murgia, Wei Ang, Aniket Mishra, Grant W Montgomery, Craig E Pennell, Phillippa M Cumberland, Ioana Cotlarciuc, Paul Mitchell, Jie Jin Wang, Maria Schache, Sarayut Janmahasatian, Sarayut Janmahasathian, Robert P Igo, Jonathan H Lass, Emily Chew, Sudha K Iyengar, Theo G M F Gorgels, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polašek, Zoran Vatavuk, James F Wilson, Brian Fleck, Tanja Zeller, Alireza Mirshahi, Christian Müller, André G Uitterlinden, Fernando Rivadeneira, Johannes R Vingerling, Albert Hofman, Ben A Oostra, Najaf Amin, Arthur A B Bergen, Yik-Ying Teo, Jugnoo S Rahi, Veronique Vitart, Cathy Williams, Paul N Baird, Tien-Yin Wong, Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver, Christopher J Hammond.
Nat. Genet.
PUBLISHED: 01-16-2013
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Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
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Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus.
Nat. Genet.
PUBLISHED: 01-06-2013
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Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
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The power of regional heritability analysis for rare and common variant detection: simulations and application to eye biometrical traits.
Front Genet
PUBLISHED: 01-01-2013
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Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits. However, they have explained relatively little trait heritability. Recently, we proposed a new analytical approach called regional heritability mapping (RHM) that captures more of the missing genetic variation. This method is applicable both to related and unrelated populations. Here, we demonstrate the power of RHM in comparison with single-SNP GWAS and gene-based association approaches under a wide range of scenarios with variable numbers of quantitative trait loci (QTL) with common and rare causal variants in a narrow genomic region. Simulations based on real genotype data were performed to assess power to capture QTL variance, and we demonstrate that RHM has greater power to detect rare variants and/or multiple alleles in a region than other approaches. In addition, we show that RHM can capture more accurately the QTL variance, when it is caused by multiple independent effects and/or rare variants. We applied RHM to analyze three biometrical eye traits for which single-SNP GWAS have been published or performed to evaluate the effectiveness of this method in real data analysis and detected some additional loci which were not detected by other GWAS methods. RHM has the potential to explain some of missing heritability by capturing variance caused by QTL with low MAF and multiple independent QTL in a region, not captured by other GWAS methods. RHM analyses can be implemented using the software REACTA (http://www.epcc.ed.ac.uk/projects-portfolio/reacta).
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SMAD7 variant rs4939827 is associated with colorectal cancer risk in Croatian population.
PLoS ONE
PUBLISHED: 01-01-2013
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Twenty common genetic variants have been associated with risk of developing colorectal cancer (CRC) in genome wide association studies to date. Since large differences between populations exist, generalisability of findings to any specific population needs to be confirmed.
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Local exome sequences facilitate imputation of less common variants and increase power of genome wide association studies.
PLoS ONE
PUBLISHED: 01-01-2013
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The analysis of less common variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association. We show that addition of population-specific exome sequence data to global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1-10%) in two very different European populations. The imputation improvement corresponds to an increase in effective sample size of 28-38%, for SNPs with a minor allele frequency in the range 1-3%.
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Individual multi-locus heterozygosity is associated with lower morning plasma cortisol concentrations.
Eur. J. Endocrinol.
PUBLISHED: 01-01-2013
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Stress is implicated as a risk factor for numerous illnesses in humans, putatively in part mediated by biological responses to stress, such as elevated cortisol concentrations. The theory of genetic homoeostasis suggests that individual heterozygosity facilitates compensation for environmental stresses. We hypothesized that heterozygosity ameliorates the biological response to a given level of perceived stress, reflected in lower plasma cortisol concentrations.
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Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.
Joanne M Murabito, Charles C White, Maryam Kavousi, Yan V Sun, Mary F Feitosa, Vijay Nambi, Claudia Lamina, Arne Schillert, Stefan Coassin, Joshua C Bis, Linda Broer, Dana C Crawford, Nora Franceschini, Ruth Frikke-Schmidt, Margot Haun, Suzanne Holewijn, Jennifer E Huffman, Shih-Jen Hwang, Stefan Kiechl, Barbara Kollerits, May E Montasser, Ilja M Nolte, Megan E Rudock, Andrea Senft, Alexander Teumer, Pim van der Harst, Veronique Vitart, Lindsay L Waite, Andrew R Wood, Christina L Wassel, Devin M Absher, Matthew A Allison, Najaf Amin, Alice Arnold, Folkert W Asselbergs, Yurii Aulchenko, Stefania Bandinelli, Maja Barbalic, Mladen Boban, Kristin Brown-Gentry, David J Couper, Michael H Criqui, Abbas Dehghan, Martin den Heijer, Benjamin Dieplinger, Jingzhong Ding, Marcus Dörr, Christine Espinola-Klein, Stephan B Felix, Luigi Ferrucci, Aaron R Folsom, Gustav Fraedrich, Quince Gibson, Robert Goodloe, Grgo Gunjaca, Meinhard Haltmayer, Gerardo Heiss, Albert Hofman, Arne Kieback, Lambertus A Kiemeney, Ivana Kolčić, Iftikhar J Kullo, Stephen B Kritchevsky, Karl J Lackner, Xiaohui Li, Wolfgang Lieb, Kurt Lohman, Christa Meisinger, David Melzer, Emile R Mohler, Ivana Mudnic, Thomas Mueller, Gerjan Navis, Friedrich Oberhollenzer, Jeffrey W Olin, Jeff O'Connell, Christopher J O'Donnell, Walter Palmas, Brenda W Penninx, Astrid Petersmann, Ozren Polašek, Bruce M Psaty, Barbara Rantner, Ken Rice, Fernando Rivadeneira, Jerome I Rotter, Adrie Seldenrijk, Marietta Stadler, Monika Summerer, Toshiko Tanaka, Anne Tybjaerg-Hansen, André G Uitterlinden, Wiek H van Gilst, Sita H Vermeulen, Sarah H Wild, Philipp S Wild, Johann Willeit, Tanja Zeller, Tatijana Zemunik, Lina Zgaga, Themistocles L Assimes, Stefan Blankenberg, Eric Boerwinkle, Harry Campbell, John P Cooke, Jacqueline de Graaf, David Herrington, Sharon L R Kardia, Braxton D Mitchell, Anna Murray, Thomas Münzel, Anne B Newman, Ben A Oostra, Igor Rudan, Alan R Shuldiner, Harold Snieder, Cornelia M van Duijn, Uwe Völker, Alan F Wright, H-Erich Wichmann, James F Wilson, Jacqueline C M Witteman, Yongmei Liu, Caroline Hayward, Ingrid B Borecki, Andreas Ziegler, Kari E North, L Adrienne Cupples, Florian Kronenberg.
Circ Cardiovasc Genet
PUBLISHED: 12-23-2011
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Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
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Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults.
Hum. Mol. Genet.
PUBLISHED: 09-09-2011
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The majority of human proteins are post-translationally modified by covalent addition of one or more complex oligosaccharides (glycans). Alterations in glycosylation processing are associated with numerous diseases and glycans are attracting increasing attention both as disease biomarkers and as targets for novel therapeutic approaches. Using a recently developed high-throughput high-performance liquid chromatography (HPLC) analysis method, we have reported, in a pilot genome-wide association study of 13 glycan features in 2705 individuals from three European populations, that polymorphisms at three loci (FUT8, FUT6/FUT3 and HNF1A) affect plasma levels of N-glycans. Here, we extended the analysis to 33 directly measured and 13 derived glycosylation traits in 3533 individuals and identified three novel gene association (MGAT5, B3GAT1 and SLC9A9) as well as replicated the previous findings using an additional European cohort. MGAT5 (meta-analysis association P-value = 1.80 × 10(-10) for rs1257220) encodes a glycosyltransferase which is known to synthesize the associated glycans. In contrast, neither B3GAT1 (rs7928758, P = 1.66 × 10(-08)) nor SLC9A9 (rs4839604, P = 3.50 × 10(-13)) had previously been associated functionally with glycosylation of plasma proteins. Given the glucuronyl transferase activity of B3GAT1, we were able to show that glucuronic acid is present on antennae of plasma glycoproteins underlying the corresponding HPLC peak. SLC9A9 encodes a proton pump which affects pH in the endosomal compartment and it was recently reported that changes in Golgi pH can impair protein sialylation, giving a possible mechanism for the observed association.
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Sequencing of high-complexity DNA pools for identification of nucleotide and structural variants in regions associated with complex traits.
Eur. J. Hum. Genet.
PUBLISHED: 08-03-2011
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We have used targeted genomic sequencing of high-complexity DNA pools based on long-range PCR and deep DNA sequencing by the SOLiD technology. The method was used for sequencing of 286 kb from four chromosomal regions with quantitative trait loci (QTL) influencing blood plasma lipid and uric acid levels in DNA pools of 500 individuals from each of five European populations. The method shows very good precision in estimating allele frequencies as compared with individual genotyping of SNPs (r(2) = 0.95, P < 10(-16)). Validation shows that the method is able to identify novel SNPs and estimate their frequency in high-complexity DNA pools. In our five populations, 17% of all SNPs and 61% of structural variants are not available in the public databases. A large fraction of the novel variants show a limited geographic distribution, with 62% of the novel SNPs and 59% of novel structural variants being detected in only one of the populations. The large number of population-specific novel SNPs underscores the need for comprehensive sequencing of local populations in order to identify the causal variants of human traits.
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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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Genetic variation in complement regulators and susceptibility to age-related macular degeneration.
Immunobiology
PUBLISHED: 05-16-2011
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Age-related macular degeneration (AMD) is the commonest cause of blindness in Western populations. Risk is influenced by age, genetic and environmental factors. Complement activation appears to be important in the pathogenesis and associations have been found between AMD and genetic variations in complement regulators such as complement factor H. We therefore investigated other complement regulators for association with AMD.
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Characterisation of genome-wide association epistasis signals for serum uric acid in human population isolates.
PLoS ONE
PUBLISHED: 05-11-2011
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Genome-wide association (GWA) studies have identified a number of loci underlying variation in human serum uric acid (SUA) levels with the SLC2A9 gene having the largest effect identified so far. Gene-gene interactions (epistasis) are largely unexplored in these GWA studies. We performed a full pair-wise genome scan in the Italian MICROS population (n?=?1201) to characterise epistasis signals in SUA levels. In the resultant epistasis profile, no SNP pairs reached the Bonferroni adjusted threshold for the pair-wise genome-wide significance. However, SLC2A9 was found interacting with multiple loci across the genome, with NFIA-SLC2A9 and SLC2A9-ESRRAP2 being significant based on a threshold derived for interactions between GWA significant SNPs and the genome and jointly explaining 8.0% of the phenotypic variance in SUA levels (3.4% by interaction components). Epistasis signal replication in a CROATIAN population (n?=?1772) was limited at the SNP level but improved dramatically at the gene ontology level. In addition, gene ontology terms enriched by the epistasis signals in each population support links between SUA levels and neurological disorders. We conclude that GWA epistasis analysis is useful despite relatively low power in small isolated populations.
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
María Soler Artigas, Daan W Loth, Louise V Wain, Sina A Gharib, Ma'en Obeidat, Wenbo Tang, Guangju Zhai, Jing Hua Zhao, Albert Vernon Smith, Jennifer E Huffman, Eva Albrecht, Catherine M Jackson, David M Evans, Gemma Cadby, Myriam Fornage, Ani Manichaikul, Lorna M Lopez, Toby Johnson, Melinda C Aldrich, Thor Aspelund, Inês Barroso, Harry Campbell, Patricia A Cassano, David J Couper, Gudny Eiriksdottir, Nora Franceschini, Melissa Garcia, Christian Gieger, Gauti Kjartan Gislason, Ivica Grković, Christopher J Hammond, Dana B Hancock, Tamara B Harris, Adaikalavan Ramasamy, Susan R Heckbert, Markku Heliövaara, Georg Homuth, Pirro G Hysi, Alan L James, Stipan Janković, Bonnie R Joubert, Stefan Karrasch, Norman Klopp, Beate Koch, Stephen B Kritchevsky, Lenore J Launer, Yongmei Liu, Laura R Loehr, Kurt Lohman, Ruth J F Loos, Thomas Lumley, Khalid A Al Balushi, Wei Q Ang, R Graham Barr, John Beilby, John D Blakey, Mladen Boban, Vesna Boraska, Jonas Brisman, John R Britton, Guy G Brusselle, Cyrus Cooper, Ivan Curjuric, Santosh Dahgam, Ian J Deary, Shah Ebrahim, Mark Eijgelsheim, Clyde Francks, Darya Gaysina, Raquel Granell, Xiangjun Gu, John L Hankinson, Rebecca Hardy, Sarah E Harris, John Henderson, Amanda Henry, Aroon D Hingorani, Albert Hofman, Patrick G Holt, Jennie Hui, Michael L Hunter, Medea Imboden, Karen A Jameson, Shona M Kerr, Ivana Kolčić, Florian Kronenberg, Jason Z Liu, Jonathan Marchini, Tricia McKeever, Andrew D Morris, Anna-Carin Olin, David J Porteous, Dirkje S Postma, Stephen S Rich, Susan M Ring, Fernando Rivadeneira, Thierry Rochat, Avan Aihie Sayer, Ian Sayers, Peter D Sly, George Davey Smith, Akshay Sood, John M Starr, André G Uitterlinden, Judith M Vonk, S Goya Wannamethee, Peter H Whincup, Cisca Wijmenga, O Dale Williams, Andrew Wong, Massimo Mangino, Kristin D Marciante, Wendy L McArdle, Bernd Meibohm, Alanna C Morrison, Kari E North, Ernst Omenaas, Lyle J Palmer, Kirsi H Pietiläinen, Isabelle Pin, Ozren Pola Sbreve Ek, Anneli Pouta, Bruce M Psaty, Anna-Liisa Hartikainen, Taina Rantanen, Samuli Ripatti, Jerome I Rotter, Igor Rudan, Alicja R Rudnicka, Holger Schulz, So-Youn Shin, Tim D Spector, Ida Surakka, Veronique Vitart, Henry Völzke, Nicholas J Wareham, Nicole M Warrington, H-Erich Wichmann, Sarah H Wild, Jemma B Wilk, Matthias Wjst, Alan F Wright, Lina Zgaga, Tatijana Zemunik, Craig E Pennell, Fredrik Nyberg, Diana Kuh, John W Holloway, H Marike Boezen, Debbie A Lawlor, Richard W Morris, Nicole Probst-Hensch, , Jaakko Kaprio, James F Wilson, Caroline Hayward, Mika Kähönen, Joachim Heinrich, Arthur W Musk, Deborah L Jarvis, Sven Gläser, Marjo-Riitta Järvelin, Bruno H Ch Stricker, Paul Elliott, George T O'Connor, David P Strachan, Stephanie J London, Ian P Hall, Vilmundur Gudnason, Martin D Tobin.
Nat. Genet.
PUBLISHED: 04-20-2011
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Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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Genetic predictors of fibrin D-dimer levels in healthy adults.
Circulation
PUBLISHED: 04-18-2011
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Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
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Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people.
Am. J. Epidemiol.
PUBLISHED: 04-15-2011
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Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ?2, ?3, and ?4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ?4 isoform with increasing age (?(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ?3 isoform (?(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ?4 homozygotes; the frequency of ?4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ?3/?4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
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Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways.
J. Med. Genet.
PUBLISHED: 04-14-2011
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Hearing is a complex trait, but until now only a few genes are known to contribute to variability of this process. In order to discover genes and pathways that underlie auditory function, a genome-wide association study was carried out within the International Consortium G-EAR.
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Does inbreeding affect N-glycosylation of human plasma proteins?
Mol. Genet. Genomics
PUBLISHED: 03-31-2011
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Inbreeding depression and heterosis are the two ends of phenotypic changes defined by the genome-wide homozygosity. The aim of this study was to investigate the association of genetic marker-based homozygosity estimates with 46 N-glycan features measured in human plasma. The study was based on a total of 2,341 subjects, originating from three isolated island communities in Croatia (Vis and Korcula islands) and Scotland (Orkney Islands). Inbreeding estimates were associated with an increase in tetrantennary and tetrasialylated glycans, and a decrease in digalactosylated glycans (P < 0.001). The strength of this association was proportional to the mean cohort-based inbreeding coefficient. Increase in tetraantennary glycans is known to be associated with various tumours and their association with inbreeding might be one of the mechanisms underlying the increased prevalence of tumours reported in some human isolated populations. Further studies are thus merited in order to confirm the association of inbreeding with changes in glycan profiles in other plant and animal populations, thus attempting to establish if glycosylation could indeed be involved in mediation of some phenotypic changes described in inbred and outbred organisms.
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Genetic architecture of circulating lipid levels.
Eur. J. Hum. Genet.
PUBLISHED: 03-30-2011
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Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
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Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.
Hum. Mutat.
PUBLISHED: 03-25-2011
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Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APO?4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APO?2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ?2 and ?4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
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CUBN is a gene locus for albuminuria.
Carsten A Böger, Ming-Huei Chen, Adrienne Tin, Matthias Olden, Anna Köttgen, Ian H de Boer, Christian Fuchsberger, Conall M O'Seaghdha, Cristian Pattaro, Alexander Teumer, Ching-Ti Liu, Nicole L Glazer, Man Li, Jeffrey R O'Connell, Toshiko Tanaka, Carmen A Peralta, Zoltan Kutalik, Jian'an Luan, Jing Hua Zhao, Shih-Jen Hwang, Ermeg Akylbekova, Holly Kramer, Pim van der Harst, Albert V Smith, Kurt Lohman, Mariza de Andrade, Caroline Hayward, Barbara Kollerits, Anke Tönjes, Thor Aspelund, Erik Ingelsson, Gudny Eiriksdottir, Lenore J Launer, Tamara B Harris, Alan R Shuldiner, Braxton D Mitchell, Dan E Arking, Nora Franceschini, Eric Boerwinkle, Josephine Egan, Dena Hernandez, Muredach Reilly, Raymond R Townsend, Thomas Lumley, David S Siscovick, Bruce M Psaty, Bryan Kestenbaum, Talin Haritunians, Sven Bergmann, Peter Vollenweider, Gérard Waeber, Vincent Mooser, Dawn Waterworth, Andrew D Johnson, Jose C Florez, James B Meigs, Xiaoning Lu, Stephen T Turner, Elizabeth J Atkinson, Tennille S Leak, Knut Aasarød, Frank Skorpen, Ann-Christine Syvänen, Thomas Illig, Jens Baumert, Wolfgang Koenig, Bernhard K Krämer, Olivier Devuyst, Josyf C Mychaleckyj, Cosetta Minelli, Stephan J L Bakker, Lyudmyla Kedenko, Bernhard Paulweber, Stefan Coassin, Karlhans Endlich, Heyo K Kroemer, Reiner Biffar, Sylvia Stracke, Henry Völzke, Michael Stumvoll, Reedik Mägi, Harry Campbell, Veronique Vitart, Nicholas D Hastie, Vilmundur Gudnason, Sharon L R Kardia, Yongmei Liu, Ozren Polašek, Gary Curhan, Florian Kronenberg, Inga Prokopenko, Igor Rudan, Johan Arnlöv, Stein Hallan, Gerjan Navis, , Afshin Parsa, Luigi Ferrucci, Josef Coresh, Michael G Shlipak, Shelley B Bull, Nicholas J Paterson, H-Erich Wichmann, Nicholas J Wareham, Ruth J F Loos, Jerome I Rotter, Peter P Pramstaller, L Adrienne Cupples, Jacques S Beckmann, Qiong Yang, Iris M Heid, Rainer Rettig, Albert W Dreisbach, Murielle Bochud, Caroline S Fox, W H L Kao.
J. Am. Soc. Nephrol.
PUBLISHED: 03-01-2011
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Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
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A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.
PLoS ONE
PUBLISHED: 02-11-2011
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Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).
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Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
Louise V Wain, Germaine C Verwoert, Paul F O'Reilly, Gang Shi, Toby Johnson, Andrew D Johnson, Murielle Bochud, Kenneth M Rice, Peter Henneman, Albert V Smith, Georg B Ehret, Najaf Amin, Martin G Larson, Vincent Mooser, David Hadley, Marcus Dörr, Joshua C Bis, Thor Aspelund, Tonu Esko, A Cecile J W Janssens, Jing Hua Zhao, Simon Heath, Maris Laan, Jingyuan Fu, Giorgio Pistis, Jian'an Luan, Pankaj Arora, Gavin Lucas, Nicola Pirastu, Irene Pichler, Anne U Jackson, Rebecca J Webster, Feng Zhang, John F Peden, Helena Schmidt, Toshiko Tanaka, Harry Campbell, Wilmar Igl, Yuri Milaneschi, Jouke-Jan Hottenga, Veronique Vitart, Daniel I Chasman, Stella Trompet, Jennifer L Bragg-Gresham, Behrooz Z Alizadeh, John C Chambers, Xiuqing Guo, Terho Lehtimäki, Brigitte Kühnel, Lorna M Lopez, Ozren Polašek, Mladen Boban, Christopher P Nelson, Alanna C Morrison, Vasyl Pihur, Santhi K Ganesh, Albert Hofman, Suman Kundu, Francesco U S Mattace-Raso, Fernando Rivadeneira, Eric J G Sijbrands, André G Uitterlinden, Shih-Jen Hwang, Ramachandran S Vasan, Thomas J Wang, Sven Bergmann, Peter Vollenweider, Gérard Waeber, Jaana Laitinen, Anneli Pouta, Paavo Zitting, Wendy L McArdle, Heyo K Kroemer, Uwe Völker, Henry Völzke, Nicole L Glazer, Kent D Taylor, Tamara B Harris, Helene Alavere, Toomas Haller, Aime Keis, Mari-Liis Tammesoo, Yurii Aulchenko, Inês Barroso, Kay-Tee Khaw, Pilar Galán, Serge Hercberg, Mark Lathrop, Susana Eyheramendy, Elin Org, Siim Sõber, Xiaowen Lu, Ilja M Nolte, Brenda W Penninx, Tanguy Corre, Corrado Masciullo, Cinzia Sala, Leif Groop, Benjamin F Voight, Olle Melander, Christopher J O'Donnell, Veikko Salomaa, Adamo Pio D'adamo, Antonella Fabretto, Flavio Faletra, Sheila Ulivi, Fabiola M Del Greco, Maurizio Facheris, Francis S Collins, Richard N Bergman, John P Beilby, Joseph Hung, A William Musk, Massimo Mangino, So-Youn Shin, Nicole Soranzo, Hugh Watkins, Anuj Goel, Anders Hamsten, Pierre Gider, Marisa Loitfelder, Marion Zeginigg, Dena Hernandez, Samer S Najjar, Pau Navarro, Sarah H Wild, Anna Maria Corsi, Andrew Singleton, Eco J C de Geus, Gonneke Willemsen, Alex N Parker, Lynda M Rose, Brendan Buckley, David Stott, Marco Orrù, Manuela Uda, , Melanie M van der Klauw, Weihua Zhang, Xinzhong Li, James Scott, Yii-Der Ida Chen, Gregory L Burke, Mika Kähönen, Jorma Viikari, Angela Döring, Thomas Meitinger, Gail Davies, John M Starr, Valur Emilsson, Andrew Plump, Jan H Lindeman, Peter A C 't Hoen, Inke R König, Janine F Felix, Robert Clarke, Jemma C Hopewell, Halit Ongen, Monique Breteler, Stéphanie Debette, Anita L Destefano, Myriam Fornage, Gary F Mitchell, Nicholas L Smith, Hilma Holm, Kari Stefansson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Nilesh J Samani, Michael Preuss, Igor Rudan, Caroline Hayward, Ian J Deary, H-Erich Wichmann, Olli T Raitakari, Walter Palmas, Jaspal S Kooner, Ronald P Stolk, J Wouter Jukema, Alan F Wright, Dorret I Boomsma, Stefania Bandinelli, Ulf B Gyllensten, James F Wilson, Luigi Ferrucci, Reinhold Schmidt, Martin Farrall, Tim D Spector, Lyle J Palmer, Jaakko Tuomilehto, Arne Pfeufer, Paolo Gasparini, David Siscovick, David Altshuler, Ruth J F Loos, Daniela Toniolo, Harold Snieder, Christian Gieger, Pierre Meneton, Nicholas J Wareham, Ben A Oostra, Andres Metspalu, Lenore Launer, Rainer Rettig, David P Strachan, Jacques S Beckmann, Jacqueline C M Witteman, Jeanette Erdmann, Ko Willems van Dijk, Eric Boerwinkle, Michael Boehnke, Paul M Ridker, Marjo-Riitta Järvelin, Aravinda Chakravarti, Gonçalo R Abecasis, Vilmundur Gudnason, Christopher Newton-Cheh, Daniel Levy, Patricia B Munroe, Bruce M Psaty, Mark J Caulfield, Dabeeru C Rao, Martin D Tobin, Paul Elliott, Cornelia M van Duijn.
Nat. Genet.
PUBLISHED: 02-10-2011
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Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
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Copy number variation across European populations.
PLoS ONE
PUBLISHED: 02-10-2011
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Genome analysis provides a powerful approach to test for evidence of genetic variation within and between geographical regions and local populations. Copy number variants which comprise insertions, deletions and duplications of genomic sequence provide one such convenient and informative source. Here, we investigate copy number variants from genome wide scans of single nucleotide polymorphisms in three European population isolates, the island of Vis in Croatia, the islands of Orkney in Scotland and the South Tyrol in Italy. We show that whereas the overall copy number variant frequencies are similar between populations, their distribution is highly specific to the population of origin, a finding which is supported by evidence for increased kinship correlation for specific copy number variants within populations.
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Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
Abbas Dehghan, Josée Dupuis, Maja Barbalic, Joshua C Bis, Gudny Eiriksdottir, Chen Lu, Niina Pellikka, Henri Wallaschofski, Johannes Kettunen, Peter Henneman, Jens Baumert, David P Strachan, Christian Fuchsberger, Veronique Vitart, James F Wilson, Guillaume Paré, Silvia Naitza, Megan E Rudock, Ida Surakka, Eco J C de Geus, Behrooz Z Alizadeh, Jack Guralnik, Alan Shuldiner, Toshiko Tanaka, Robert Y L Zee, Renate B Schnabel, Vijay Nambi, Maryam Kavousi, Samuli Ripatti, Matthias Nauck, Nicholas L Smith, Albert V Smith, Jouko Sundvall, Paul Scheet, Yongmei Liu, Aimo Ruokonen, Lynda M Rose, Martin G Larson, Ron C Hoogeveen, Nelson B Freimer, Alexander Teumer, Russell P Tracy, Lenore J Launer, Julie E Buring, Jennifer F Yamamoto, Aaron R Folsom, Eric J G Sijbrands, James Pankow, Paul Elliott, John F Keaney, Wei Sun, Antti-Pekka Sarin, João D Fontes, Sunita Badola, Brad C Astor, Albert Hofman, Anneli Pouta, Karl Werdan, Karin H Greiser, Oliver Kuss, Henriette E Meyer Zu Schwabedissen, Joachim Thiery, Yalda Jamshidi, Ilja M Nolte, Nicole Soranzo, Timothy D Spector, Henry Völzke, Alexander N Parker, Thor Aspelund, David Bates, Lauren Young, Kim Tsui, David S Siscovick, Xiuqing Guo, Jerome I Rotter, Manuela Uda, David Schlessinger, Igor Rudan, Andrew A Hicks, Brenda W Penninx, Barbara Thorand, Christian Gieger, Joe Coresh, Gonneke Willemsen, Tamara B Harris, André G Uitterlinden, Marjo-Riitta Järvelin, Kenneth Rice, Dörte Radke, Veikko Salomaa, Ko Willems van Dijk, Eric Boerwinkle, Ramachandran S Vasan, Luigi Ferrucci, Quince D Gibson, Stefania Bandinelli, Harold Snieder, Dorret I Boomsma, Xiangjun Xiao, Harry Campbell, Caroline Hayward, Peter P Pramstaller, Cornelia M van Duijn, Leena Peltonen, Bruce M Psaty, Vilmundur Gudnason, Paul M Ridker, Georg Homuth, Wolfgang Koenig, Christie M Ballantyne, Jacqueline C M Witteman, Emelia J Benjamin, Markus Perola, Daniel I Chasman.
Circulation
PUBLISHED: 02-07-2011
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C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.
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Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.
Joshua C Bis, Maryam Kavousi, Nora Franceschini, Aaron Isaacs, Gonçalo R Abecasis, Ulf Schminke, Wendy S Post, Albert V Smith, L Adrienne Cupples, Hugh S Markus, Reinhold Schmidt, Jennifer E Huffman, Terho Lehtimäki, Jens Baumert, Thomas Münzel, Susan R Heckbert, Abbas Dehghan, Kari North, Ben Oostra, Steve Bevan, Eva-Maria Stoegerer, Caroline Hayward, Olli Raitakari, Christa Meisinger, Arne Schillert, Serena Sanna, Henry Völzke, Yu-Ching Cheng, Bolli Thorsson, Caroline S Fox, Kenneth Rice, Fernando Rivadeneira, Vijay Nambi, Eran Halperin, Katja E Petrovic, Leena Peltonen, H Erich Wichmann, Renate B Schnabel, Marcus Dörr, Afshin Parsa, Thor Aspelund, Serkalem Demissie, Sekar Kathiresan, Muredach P Reilly, Kent Taylor, André Uitterlinden, David J Couper, Matthias Sitzer, Mika Kähönen, Thomas Illig, Philipp S Wild, Marco Orrù, Jan Lüdemann, Alan R Shuldiner, Gudny Eiriksdottir, Charles C White, Jerome I Rotter, Albert Hofman, Jochen Seissler, Tanja Zeller, Gianluca Usala, Florian Ernst, Lenore J Launer, Ralph B D'Agostino, Daniel H O'Leary, Christie Ballantyne, Joachim Thiery, Andreas Ziegler, Edward G Lakatta, Ravi Kumar Chilukoti, Tamara B Harris, Philip A Wolf, Bruce M Psaty, Joseph F Polak, Xia Li, Wolfgang Rathmann, Manuela Uda, Eric Boerwinkle, Norman Klopp, Helena Schmidt, James F Wilson, Jorma Viikari, Wolfgang Koenig, Stefan Blankenberg, Anne B Newman, Jacqueline Witteman, Gerardo Heiss, Cornelia van Duijn, Angelo Scuteri, Georg Homuth, Braxton D Mitchell, Vilmundur Gudnason, Christopher J O'Donnell, .
Nat. Genet.
PUBLISHED: 02-02-2011
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Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.