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Find video protocols related to scientific articles indexed in Pubmed.
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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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
Nat. Genet.
PUBLISHED: 02-10-2014
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Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
, Anubha Mahajan, Min Jin Go, Weihua Zhang, Jennifer E Below, Kyle J Gaulton, Teresa Ferreira, Momoko Horikoshi, Andrew D Johnson, Maggie C Y Ng, Inga Prokopenko, Danish Saleheen, Xu Wang, Eleftheria Zeggini, Gonçalo R Abecasis, Linda S Adair, Peter Almgren, Mustafa Atalay, Tin Aung, Damiano Baldassarre, Beverley Balkau, Yuqian Bao, Anthony H Barnett, Inês Barroso, Abdul Basit, Latonya F Been, John Beilby, Graeme I Bell, Rafn Benediktsson, Richard N Bergman, Bernhard O Boehm, Eric Boerwinkle, Lori L Bonnycastle, Noel Burtt, Qiuyin Cai, Harry Campbell, Jason Carey, Stéphane Cauchi, Mark Caulfield, Juliana C N Chan, Li-Ching Chang, Tien-Jyun Chang, Yi-Cheng Chang, Guillaume Charpentier, Chien-Hsiun Chen, Han Chen, Yuan-Tsong Chen, Kee-Seng Chia, Manickam Chidambaram, Peter S Chines, Nam H Cho, Young Min Cho, Lee-Ming Chuang, Francis S Collins, Marylin C Cornelis, David J Couper, Andrew T Crenshaw, Rob M Van Dam, John Danesh, Debashish Das, Ulf de Faire, George Dedoussis, Panos Deloukas, Antigone S Dimas, Christian Dina, Alex S Doney, Peter J Donnelly, Mozhgan Dorkhan, Cornelia van Duijn, Josée Dupuis, Sarah Edkins, Paul Elliott, Valur Emilsson, Raimund Erbel, Johan G Eriksson, Jorge Escobedo, Tonu Esko, Elodie Eury, Jose C Florez, Pierre Fontanillas, Nita G Forouhi, Tom Forsén, Caroline Fox, Ross M Fraser, Timothy M Frayling, Philippe Froguel, Philippe Frossard, Yutang Gao, Karl Gertow, Christian Gieger, Bruna Gigante, Harald Grallert, George B Grant, Leif C Grrop, Chrisropher J Groves, Elin Grundberg, Candace Guiducci, Anders Hamsten, Bok-Ghee Han, Kazuo Hara, Neelam Hassanali, Andrew T Hattersley, Caroline Hayward, Asa K Hedman, Christian Herder, Albert Hofman, Oddgeir L Holmen, Kees Hovingh, Astradur B Hreidarsson, Cheng Hu, Frank B Hu, Jennie Hui, Steve E Humphries, Sarah E Hunt, David J Hunter, Kristian Hveem, Zafar I Hydrie, Hiroshi Ikegami, Thomas Illig, Erik Ingelsson, Muhammed Islam, Bo Isomaa, Anne U Jackson, Tazeen Jafar, Alan James, Weiping Jia, Karl-Heinz Jöckel, Anna Jonsson, Jeremy B M Jowett, Takashi Kadowaki, Hyun Min Kang, Stavroula Kanoni, Wen Hong L Kao, Sekar Kathiresan, Norihiro Kato, Prasad Katulanda, Kirkka M Keinanen-Kiukaanniemi, Ann M Kelly, Hassan Khan, Kay-Tee Khaw, Chiea-Chuen Khor, Hyung-Lae Kim, Sangsoo Kim, Young Jin Kim, Leena Kinnunen, Norman Klopp, Augustine Kong, Eeva Korpi-Hyövälti, Sudhir Kowlessur, Peter Kraft, Jasmina Kravic, Malene M Kristensen, S Krithika, Ashish Kumar, Jesus Kumate, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Vasiliki Lagou, Timo A Lakka, Claudia Langenberg, Cordelia Langford, Robert Lawrence, Karin Leander, Jen-Mai Lee, Nanette R Lee, Man Li, Xinzhong Li, Yun Li, Junbin Liang, Samuel Liju, Wei-Yen Lim, Lars Lind, Cecilia M Lindgren, Eero Lindholm, Ching-Ti Liu, Jian Jun Liu, Stéphane Lobbens, Jirong Long, Ruth J F Loos, Wei Lu, Jian'an Luan, Valeriya Lyssenko, Ronald C W Ma, Shiro Maeda, Reedik Mägi, Satu Mannisto, David R Matthews, James B Meigs, Olle Melander, Andres Metspalu, Julia Meyer, Ghazala Mirza, Evelin Mihailov, Susanne Moebus, Viswanathan Mohan, Karen L Mohlke, Andrew D Morris, Thomas W Mühleisen, Martina Müller-Nurasyid, Bill Musk, Jiro Nakamura, Eitaro Nakashima, Pau Navarro, Peng-Keat Ng, Alexandra C Nica, Peter M Nilsson, Inger Njølstad, Markus M Nöthen, Keizo Ohnaka, Twee Hee Ong, Katharine R Owen, Colin N A Palmer, James S Pankow, Kyong Soo Park, Melissa Parkin, Sonali Pechlivanis, Nancy L Pedersen, Leena Peltonen, John R B Perry, Annette Peters, Janini M Pinidiyapathirage, Carl G Platou, Simon Potter, Jackie F Price, Lu Qi, Venkatesan Radha, Loukianos Rallidis, Asif Rasheed, Wolfgang Rathman, Rainer Rauramaa, Soumya Raychaudhuri, N William Rayner, Simon D Rees, Emil Rehnberg, Samuli Ripatti, Neil Robertson, Michael Roden, Elizabeth J Rossin, Igor Rudan, Denis Rybin, Timo E Saaristo, Veikko Salomaa, Juha Saltevo, Maria Samuel, Dharambir K Sanghera, Jouko Saramies, James Scott, Laura J Scott, Robert A Scott, Ayellet V Segrè, Joban Sehmi, Bengt Sennblad, Nabi Shah, Sonia Shah, A Samad Shera, Xiao Ou Shu, Alan R Shuldiner, Gunnar Sigurđsson, Eric Sijbrands, Angela Silveira, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S Small, Wing Yee So, Alena Stančáková, Kari Stefansson, Gerald Steinbach, Valgerdur Steinthorsdottir, Kathleen Stirrups, Rona J Strawbridge, Heather M Stringham, Qi Sun, Chen Suo, Ann-Christine Syvänen, Ryoichi Takayanagi, Fumihiko Takeuchi, Wan Ting Tay, Tanya M Teslovich, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Emmi Tikkanen, Joseph Trakalo, Elena Tremoli, Mieke D Trip, Fuu Jen Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, André G Uitterlinden, Adán Valladares-Salgado, Sailaja Vedantam, Fabrizio Veglia, Benjamin F Voight, Congrong Wang, Nicholas J Wareham, Roman Wennauer, Ananda R Wickremasinghe, Tom Wilsgaard, James F Wilson, Steven Wiltshire, Wendy Winckler, Tien Yin Wong, Andrew R Wood, Jer-Yuarn Wu, Ying Wu, Ken Yamamoto, Toshimasa Yamauchi, Mingyu Yang, Loïc Yengo, Mitsuhiro Yokota, Robin Young, Delilah Zabaneh, Fan Zhang, Rong Zhang, Wei Zheng, Paul Z Zimmet, David Altshuler, Donald W Bowden, Yoon Shin Cho, Nancy J Cox, Miguel Cruz, Craig L Hanis, Jaspal Kooner, Jong-Young Lee, Mark Seielstad, Yik Ying Teo, Michael Boehnke, Esteban J Parra, Jonh C Chambers, E Shyong Tai, Mark I McCarthy, Andrew P Morris.
Nat. Genet.
PUBLISHED: 01-17-2014
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To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
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Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.
Nat. Genet.
PUBLISHED: 01-06-2014
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Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).
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The role of adiposity in cardiometabolic traits: a mendelian randomization analysis.
Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H M Draisma, Janina S Ried, Natalie R Van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P Nelson, Natalia V Rivera, Kati Kristiansson, Huei-Yi Shen, Aki S Havulinna, Abbas Dehghan, Louise A Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tonu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C Karssen, Johannes Kettunen, Wolfgang Koenig, Kari Kuulasmaa, Tiina Laatikainen, Jaana Laitinen, Cecilia Lindgren, Valeriya Lyssenko, Esa Läärä, Nigel W Rayner, Satu Mannisto, Anneli Pouta, Wolfgang Rathmann, Fernando Rivadeneira, Aimo Ruokonen, Markku J Savolainen, Eric J G Sijbrands, Kerrin S Small, Jan H Smit, Valgerdur Steinthorsdottir, Ann-Christine Syvänen, Anja Taanila, Martin D Tobin, André G Uitterlinden, Sara M Willems, Gonneke Willemsen, Jacqueline Witteman, Markus Perola, Alun Evans, Jean Ferrières, Jarmo Virtamo, Frank Kee, David-Alexandre Trégouët, Dominique Arveiler, Philippe Amouyel, Marco M Ferrario, Paolo Brambilla, Alistair S Hall, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, John B Whitfield, Antti Jula, Paul Knekt, Ben Oostra, Cornelia M van Duijn, Brenda W J H Penninx, George Davey Smith, Jaakko Kaprio, Nilesh J Samani, Christian Gieger, Annette Peters, H Erich Wichmann, Dorret I Boomsma, Eco J C de Geus, Tiinamaija Tuomi, Chris Power, Christopher J Hammond, Tim D Spector, Lars Lind, Marju Orho-Melander, Colin Neil Alexander Palmer, Andrew D Morris, Leif Groop, Marjo-Riitta Järvelin, Veikko Salomaa, Erkki Vartiainen, Albert Hofman, Samuli Ripatti, Andres Metspalu, Unnur Thorsteinsdottir, Kari Stefansson, Nancy L Pedersen, Mark I McCarthy, Erik Ingelsson, Inga Prokopenko, .
PLoS Med.
PUBLISHED: 06-01-2013
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The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
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Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets.
PLoS Genet.
PUBLISHED: 06-01-2013
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Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimers disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
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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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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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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
Simon N Stacey, Patrick Sulem, Aslaug Jonasdottir, Gisli Masson, Julius Gudmundsson, Daniel F Gudbjartsson, Olafur T Magnusson, Sigurjon A Gudjonsson, Bardur Sigurgeirsson, Kristin Thorisdottir, Rafn Ragnarsson, Kristrun R Benediktsdottir, Bjørn A Nexø, Anne Tjønneland, Kim Overvad, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Kari Hemminki, Cristina Corredera, Victoria Fuentelsaz, Pilar Grasa, Sebastian Navarrete, Fernando Fuertes, Maria D Garcia-Prats, Enrique Sanambrosio, Angeles Panadero, Ana De Juan, Almudena García, Fernando Rivera, Dolores Planelles, Virtudes Soriano, Celia Requena, Katja K Aben, Michelle M van Rossum, Ruben G H M Cremers, Inge M van Oort, Dick-Johan van Spronsen, Jack A Schalken, Wilbert H M Peters, Brian T Helfand, Jenny L Donovan, Freddie C Hamdy, Daniel Badescu, Ovidiu Codreanu, Mariana Jinga, Irma E Csiki, Vali Constantinescu, Paula Badea, Ioan N Mates, Daniela E Dinu, Adrian Constantin, Dana Mates, Sjofn Kristjansdottir, Bjarni A Agnarsson, Eirikur Jonsson, Rosa B Barkardottir, Gudmundur V Einarsson, Fridbjorn Sigurdsson, Pall H Moller, Tryggvi Stefansson, Trausti Valdimarsson, Oskar T Johannsson, Helgi Sigurdsson, Thorvaldur Jonsson, Jon G Jonasson, Laufey Tryggvadóttir, Terri Rice, Helen M Hansen, Yuanyuan Xiao, Daniel H Lachance, Brian Patrick O Neill, Matthew L Kosel, Paul A Decker, Gudmar Thorleifsson, Hrefna Johannsdottir, Hafdis T Helgadottir, Asgeir Sigurdsson, Valgerdur Steinthorsdottir, Annika Lindblom, , Robert S Sandler, Temitope O Keku, Karina Banasik, Torben Jørgensen, Daniel R Witte, Torben Hansen, Oluf Pedersen, Viorel Jinga, David E Neal, William J Catalona, Margaret Wrensch, John Wiencke, Robert B Jenkins, Eduardo Nagore, Ulla Vogel, Lambertus A Kiemeney, Rajiv Kumar, Jose I Mayordomo, Jon H Olafsson, Augustine Kong, Unnur Thorsteinsdottir, Thorunn Rafnar, Kari Stefansson.
Nat. Genet.
PUBLISHED: 05-27-2011
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To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3 untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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Common variants at 10 genomic loci influence hemoglobin A?(C) levels via glycemic and nonglycemic pathways.
Nicole Soranzo, Serena Sanna, Eleanor Wheeler, Christian Gieger, Dörte Radke, Josée Dupuis, Nabila Bouatia-Naji, Claudia Langenberg, Inga Prokopenko, Elliot Stolerman, Manjinder S Sandhu, Matthew M Heeney, Joseph M Devaney, Muredach P Reilly, Sally L Ricketts, Alexandre F R Stewart, Benjamin F Voight, Christina Willenborg, Benjamin Wright, David Altshuler, Dan Arking, Beverley Balkau, Daniel Barnes, Eric Boerwinkle, Bernhard Böhm, Amélie Bonnefond, Lori L Bonnycastle, Dorret I Boomsma, Stefan R Bornstein, Yvonne Böttcher, Suzannah Bumpstead, Mary Susan Burnett-Miller, Harry Campbell, Antonio Cao, John Chambers, Robert Clark, Francis S Collins, Josef Coresh, Eco J C de Geus, Mariano Dei, Panos Deloukas, Angela Döring, Josephine M Egan, Roberto Elosua, Luigi Ferrucci, Nita Forouhi, Caroline S Fox, Christopher Franklin, Maria Grazia Franzosi, Sophie Gallina, Anuj Goel, Jurgen Graessler, Harald Grallert, Andreas Greinacher, David Hadley, Alistair Hall, Anders Hamsten, Caroline Hayward, Simon Heath, Christian Herder, Georg Homuth, Jouke-Jan Hottenga, Rachel Hunter-Merrill, Thomas Illig, Anne U Jackson, Antti Jula, Marcus Kleber, Christopher W Knouff, Augustine Kong, Jaspal Kooner, Anna Köttgen, Peter Kovacs, Knut Krohn, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Mark Lathrop, Cécile Lecoeur, Man Li, Mingyao Li, Ruth J F Loos, Jian'an Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K E Magnusson, Anders Malarstig, Massimo Mangino, María Teresa Martínez-Larrad, Winfried März, Wendy L McArdle, Ruth McPherson, Christa Meisinger, Thomas Meitinger, Olle Melander, Karen L Mohlke, Vincent E Mooser, Mario A Morken, Narisu Narisu, David M Nathan, Matthias Nauck, Chris O'Donnell, Konrad Oexle, Nazario Olla, James S Pankow, Felicity Payne, John F Peden, Nancy L Pedersen, Leena Peltonen, Markus Perola, Ozren Polašek, Eleonora Porcu, Daniel J Rader, Wolfgang Rathmann, Samuli Ripatti, Ghislain Rocheleau, Michael Roden, Igor Rudan, Veikko Salomaa, Richa Saxena, David Schlessinger, Heribert Schunkert, Peter Schwarz, Udo Seedorf, Elizabeth Selvin, Manuel Serrano-Ríos, Peter Shrader, Angela Silveira, David Siscovick, Kjioung Song, Timothy D Spector, Kari Stefansson, Valgerdur Steinthorsdottir, David P Strachan, Rona Strawbridge, Michael Stumvoll, Ida Surakka, Amy J Swift, Toshiko Tanaka, Alexander Teumer, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Anke Tönjes, Gianluca Usala, Veronique Vitart, Henry Völzke, Henri Wallaschofski, Dawn M Waterworth, Hugh Watkins, H-Erich Wichmann, Sarah H Wild, Gonneke Willemsen, Gordon H Williams, James F Wilson, Juliane Winkelmann, Alan F Wright, , Carina Zabena, Jing Hua Zhao, Stephen E Epstein, Jeanette Erdmann, Hakon H Hakonarson, Sekar Kathiresan, Kay-Tee Khaw, Robert Roberts, Nilesh J Samani, Mark D Fleming, Robert Sladek, Goncalo Abecasis, Michael Boehnke, Philippe Froguel, Leif Groop, Mark I McCarthy, W H Linda Kao, Jose C Florez, Manuela Uda, Nicholas J Wareham, Inês Barroso, James B Meigs.
Diabetes
PUBLISHED: 09-21-2010
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Glycated hemoglobin (HbA?(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA?(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA?(c) levels.
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Evaluating differences in linkage disequilibrium between populations.
Ann. Hum. Genet.
PUBLISHED: 06-10-2010
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We propose two methods to evaluate the statistical significance of differences in linkage disequilibrium (LD) between populations, where LD is measured by the standardised parameter D. The first method is based on bootstrapping individuals within populations in order to test LD differences for each pair of loci. Using this approach we propose a solution to the problem of testing multiple locus-pairs by means of a single test for the number of pairs that exhibit significant LD differences among populations. The second method provides the Bayesian posterior probability that one population has greater LD than the other for each locus pair. Both methods can handle genotypes with unknown phase, and are demonstrated using two data sets. For the purpose of demonstration, we apply the methods to two different sets of data from humans. First, we explore the issue of LD differences between reproductively isolated populations using a new data set of twelve Xq25 microsatellites, typed in four European populations. Second, we examine evidence for LD differences between Alzheimer cases and controls from the Icelandic population using 19 single nucleotide polymorphisms (SNPs) from a 97 kb region flanking the Apolipoprotein E (APOE) gene on chromosome 19.
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
Elizabeth K Speliotes, Cristen J Willer, Sonja I Berndt, Keri L Monda, Gudmar Thorleifsson, Anne U Jackson, Hana Lango Allen, Cecilia M Lindgren, Jian'an Luan, Reedik Mägi, Joshua C Randall, Sailaja Vedantam, Thomas W Winkler, Lu Qi, Tsegaselassie Workalemahu, Iris M Heid, Valgerdur Steinthorsdottir, Heather M Stringham, Michael N Weedon, Eleanor Wheeler, Andrew R Wood, Teresa Ferreira, Robert J Weyant, Ayellet V Segrè, Karol Estrada, Liming Liang, James Nemesh, Ju-Hyun Park, Stefan Gustafsson, Tuomas O Kilpeläinen, Jian Yang, Nabila Bouatia-Naji, Tonu Esko, Mary F Feitosa, Zoltan Kutalik, Massimo Mangino, Soumya Raychaudhuri, André Scherag, Albert Vernon Smith, Ryan Welch, Jing Hua Zhao, Katja K Aben, Devin M Absher, Najaf Amin, Anna L Dixon, Eva Fisher, Nicole L Glazer, Michael E Goddard, Nancy L Heard-Costa, Volker Hoesel, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Shamika Ketkar, Claudia Lamina, Shengxu Li, Miriam F Moffatt, Richard H Myers, Narisu Narisu, John R B Perry, Marjolein J Peters, Michael Preuss, Samuli Ripatti, Fernando Rivadeneira, Camilla Sandholt, Laura J Scott, Nicholas J Timpson, Jonathan P Tyrer, Sophie van Wingerden, Richard M Watanabe, Charles C White, Fredrik Wiklund, Christina Barlassina, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Robert W Lawrence, Niina Pellikka, Inga Prokopenko, Jianxin Shi, Elisabeth Thiering, Helene Alavere, Maria T S Alibrandi, Peter Almgren, Alice M Arnold, Thor Aspelund, Larry D Atwood, Beverley Balkau, Anthony J Balmforth, Amanda J Bennett, Yoav Ben-Shlomo, Richard N Bergman, Sven Bergmann, Heike Biebermann, Alexandra I F Blakemore, Tanja Boes, Lori L Bonnycastle, Stefan R Bornstein, Morris J Brown, Thomas A Buchanan, Fabio Busonero, Harry Campbell, Francesco P Cappuccio, Christine Cavalcanti-Proença, Yii-Der Ida Chen, Chih-Mei Chen, Peter S Chines, Robert Clarke, Lachlan Coin, John Connell, Ian N M Day, Martin den Heijer, Jubao Duan, Shah Ebrahim, Paul Elliott, Roberto Elosua, Gudny Eiriksdottir, Michael R Erdos, Johan G Eriksson, Maurizio F Facheris, Stephan B Felix, Pamela Fischer-Posovszky, Aaron R Folsom, Nele Friedrich, Nelson B Freimer, Mao Fu, Stefan Gaget, Pablo V Gejman, Eco J C Geus, Christian Gieger, Anette P Gjesing, Anuj Goel, Philippe Goyette, Harald Grallert, Jürgen Gräßler, Danielle M Greenawalt, Christopher J Groves, Vilmundur Gudnason, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Alistair S Hall, Aki S Havulinna, Caroline Hayward, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Anke Hinney, Albert Hofman, Georg Homuth, Jennie Hui, Wilmar Igl, Carlos Iribarren, Bo Isomaa, Kevin B Jacobs, Ivonne Jarick, Elizabeth Jewell, Ulrich John, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Marika Kaakinen, Eero Kajantie, Lee M Kaplan, Sekar Kathiresan, Johannes Kettunen, Leena Kinnunen, Joshua W Knowles, Ivana Kolčić, Inke R König, Seppo Koskinen, Peter Kovacs, Johanna Kuusisto, Peter Kraft, Kirsti Kvaløy, Jaana Laitinen, Olivier Lantieri, Chiara Lanzani, Lenore J Launer, Cécile Lecoeur, Terho Lehtimäki, Guillaume Lettre, Jianjun Liu, Marja-Liisa Lokki, Mattias Lorentzon, Robert N Luben, Barbara Ludwig, , Paolo Manunta, Diana Marek, Michel Marre, Nicholas G Martin, Wendy L McArdle, Anne McCarthy, Barbara McKnight, Thomas Meitinger, Olle Melander, David Meyre, Kristian Midthjell, Grant W Montgomery, Mario A Morken, Andrew P Morris, Rosanda Mulić, Julius S Ngwa, Mari Nelis, Matt J Neville, Dale R Nyholt, Christopher J O'Donnell, Stephen O'Rahilly, Ken K Ong, Ben Oostra, Guillaume Paré, Alex N Parker, Markus Perola, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Ozren Polašek, Anneli Pouta, Suzanne Rafelt, Olli Raitakari, Nigel W Rayner, Martin Ridderstråle, Winfried Rief, Aimo Ruokonen, Neil R Robertson, Peter Rzehak, Veikko Salomaa, Alan R Sanders, Manjinder S Sandhu, Serena Sanna, Jouko Saramies, Markku J Savolainen, Susann Scherag, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, Kaisa Silander, Juha Sinisalo, David S Siscovick, Jan H Smit, Nicole Soranzo, Ulla Sovio, Jonathan Stephens, Ida Surakka, Amy J Swift, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Tanya M Teslovich, John R Thompson, Brian Thomson, Anke Tönjes, Tiinamaija Tuomi, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Jorma Viikari, Sophie Visvikis-Siest, Veronique Vitart, Carla I G Vogel, Benjamin F Voight, Lindsay L Waite, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Susanna Wiegand, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Jacqueline C Witteman, Jianfeng Xu, Qunyuan Zhang, Lina Zgaga, Andreas Ziegler, Paavo Zitting, John P Beilby, I Sadaf Farooqi, Johannes Hebebrand, Heikki V Huikuri, Alan L James, Mika Kähönen, Douglas F Levinson, Fabio Macciardi, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Paul M Ridker, Michael Stumvoll, Jacques S Beckmann, Heiner Boeing, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, Francis S Collins, L Adrienne Cupples, George Davey Smith, Jeanette Erdmann, Philippe Froguel, Henrik Grönberg, Ulf Gyllensten, Per Hall, Torben Hansen, Tamara B Harris, Andrew T Hattersley, Richard B Hayes, Joachim Heinrich, Frank B Hu, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Jaakko Kaprio, Fredrik Karpe, Kay-Tee Khaw, Lambertus A Kiemeney, Heiko Krude, Markku Laakso, Debbie A Lawlor, Andres Metspalu, Patricia B Munroe, Willem H Ouwehand, Oluf Pedersen, Brenda W Penninx, Annette Peters, Peter P Pramstaller, Thomas Quertermous, Thomas Reinehr, Aila Rissanen, Igor Rudan, Nilesh J Samani, Peter E H Schwarz, Alan R Shuldiner, Timothy D Spector, Jaakko Tuomilehto, Manuela Uda, André Uitterlinden, Timo T Valle, Martin Wabitsch, Gérard Waeber, Nicholas J Wareham, Hugh Watkins, James F Wilson, Alan F Wright, M Carola Zillikens, Nilanjan Chatterjee, Steven A McCarroll, Shaun Purcell, Eric E Schadt, Peter M Visscher, Themistocles L Assimes, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Karen L Mohlke, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Cornelia M van Duijn, H-Erich Wichmann, Timothy M Frayling, Unnur Thorsteinsdottir, Gonçalo R Abecasis, Inês Barroso, Michael Boehnke, Kari Stefansson, Kari E North, Mark I McCarthy, Joel N Hirschhorn, Erik Ingelsson, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 05-13-2010
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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ? 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
Iris M Heid, Anne U Jackson, Joshua C Randall, Thomas W Winkler, Lu Qi, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, M Carola Zillikens, Elizabeth K Speliotes, Reedik Mägi, Tsegaselassie Workalemahu, Charles C White, Nabila Bouatia-Naji, Tamara B Harris, Sonja I Berndt, Erik Ingelsson, Cristen J Willer, Michael N Weedon, Jian'an Luan, Sailaja Vedantam, Tonu Esko, Tuomas O Kilpeläinen, Zoltan Kutalik, Shengxu Li, Keri L Monda, Anna L Dixon, Christopher C Holmes, Lee M Kaplan, Liming Liang, Josine L Min, Miriam F Moffatt, Cliona Molony, George Nicholson, Eric E Schadt, Krina T Zondervan, Mary F Feitosa, Teresa Ferreira, Hana Lango Allen, Robert J Weyant, Eleanor Wheeler, Andrew R Wood, , Karol Estrada, Michael E Goddard, Guillaume Lettre, Massimo Mangino, Dale R Nyholt, Shaun Purcell, Albert Vernon Smith, Peter M Visscher, Jian Yang, Steven A McCarroll, James Nemesh, Benjamin F Voight, Devin Absher, Najaf Amin, Thor Aspelund, Lachlan Coin, Nicole L Glazer, Caroline Hayward, Nancy L Heard-Costa, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Marika Kaakinen, Karen Kapur, Shamika Ketkar, Joshua W Knowles, Peter Kraft, Aldi T Kraja, Claudia Lamina, Michael F Leitzmann, Barbara McKnight, Andrew P Morris, Ken K Ong, John R B Perry, Marjolein J Peters, Ozren Polašek, Inga Prokopenko, Nigel W Rayner, Samuli Ripatti, Fernando Rivadeneira, Neil R Robertson, Serena Sanna, Ulla Sovio, Ida Surakka, Alexander Teumer, Sophie van Wingerden, Veronique Vitart, Jing Hua Zhao, Christine Cavalcanti-Proença, Peter S Chines, Eva Fisher, Jennifer R Kulzer, Cécile Lecoeur, Narisu Narisu, Camilla Sandholt, Laura J Scott, Kaisa Silander, Klaus Stark, Mari-Liis Tammesoo, Tanya M Teslovich, Nicholas John Timpson, Richard M Watanabe, Ryan Welch, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Johannes Kettunen, Robert W Lawrence, Niina Pellikka, Markus Perola, Liesbeth Vandenput, Helene Alavere, Peter Almgren, Larry D Atwood, Amanda J Bennett, Reiner Biffar, Lori L Bonnycastle, Stefan R Bornstein, Thomas A Buchanan, Harry Campbell, Ian N M Day, Mariano Dei, Marcus Dörr, Paul Elliott, Michael R Erdos, Johan G Eriksson, Nelson B Freimer, Mao Fu, Stefan Gaget, Eco J C Geus, Anette P Gjesing, Harald Grallert, Jürgen Gräßler, Christopher J Groves, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Aki S Havulinna, Karl-Heinz Herzig, Andrew A Hicks, Jennie Hui, Wilmar Igl, Pekka Jousilahti, Antti Jula, Eero Kajantie, Leena Kinnunen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Heyo K Kroemer, Vjekoslav Krželj, Johanna Kuusisto, Kirsti Kvaloy, Jaana Laitinen, Olivier Lantieri, G Mark Lathrop, Marja-Liisa Lokki, Robert N Luben, Barbara Ludwig, Wendy L McArdle, Anne McCarthy, Mario A Morken, Mari Nelis, Matt J Neville, Guillaume Paré, Alex N Parker, John F Peden, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Anneli Pouta, Martin Ridderstråle, Nilesh J Samani, Jouko Saramies, Juha Sinisalo, Jan H Smit, Rona J Strawbridge, Heather M Stringham, Amy J Swift, Maris Teder-Laving, Brian Thomson, Gianluca Usala, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Claudia B Volpato, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Lina Zgaga, Paavo Zitting, John P Beilby, Alan L James, Mika Kähönen, Terho Lehtimäki, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Olli Raitakari, Paul M Ridker, Michael Stumvoll, Anke Tönjes, Jorma Viikari, Beverley Balkau, Yoav Ben-Shlomo, Richard N Bergman, Heiner Boeing, George Davey Smith, Shah Ebrahim, Philippe Froguel, Torben Hansen, Christian Hengstenberg, Kristian Hveem, Bo Isomaa, Torben Jørgensen, Fredrik Karpe, Kay-Tee Khaw, Markku Laakso, Debbie A Lawlor, Michel Marre, Thomas Meitinger, Andres Metspalu, Kristian Midthjell, Oluf Pedersen, Veikko Salomaa, Peter E H Schwarz, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T Valle, Nicholas J Wareham, Alice M Arnold, Jacques S Beckmann, Sven Bergmann, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Francis S Collins, Gudny Eiriksdottir, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Andrew T Hattersley, Albert Hofman, Frank B Hu, Thomas Illig, Carlos Iribarren, Marjo-Riitta Järvelin, W H Linda Kao, Jaakko Kaprio, Lenore J Launer, Patricia B Munroe, Ben Oostra, Brenda W Penninx, Peter P Pramstaller, Bruce M Psaty, Thomas Quertermous, Aila Rissanen, Igor Rudan, Alan R Shuldiner, Nicole Soranzo, Timothy D Spector, Ann-Christine Syvänen, Manuela Uda, André Uitterlinden, Henry Völzke, Peter Vollenweider, James F Wilson, Jacqueline C Witteman, Alan F Wright, Gonçalo R Abecasis, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Timothy M Frayling, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Kari E North, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Joel N Hirschhorn, Themistocles L Assimes, H-Erich Wichmann, Unnur Thorsteinsdottir, Cornelia M van Duijn, Kari Stefansson, L Adrienne Cupples, Ruth J F Loos, Inês Barroso, Mark I McCarthy, Caroline S Fox, Karen L Mohlke, Cecilia M Lindgren.
Nat. Genet.
PUBLISHED: 05-06-2010
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Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?³ to P = 1.2 × 10?¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hana Lango Allen, Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tonu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltan Kutalik, Keri L Monda, Ozren Polašek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marušić, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Järvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn.
Nature
PUBLISHED: 04-23-2010
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Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?
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Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.
Solveig Gretarsdottir, Annette F Baas, Gudmar Thorleifsson, Hilma Holm, Martin den Heijer, Jean-Paul P M de Vries, Steef E Kranendonk, Clark J A M Zeebregts, Steven M van Sterkenburg, Robert H Geelkerken, Andre M van Rij, Michael J A Williams, Albert P M Boll, Jelena P Kostic, Adalbjorg Jonasdottir, Aslaug Jonasdottir, G Bragi Walters, Gisli Masson, Patrick Sulem, Jona Saemundsdottir, Magali Mouy, Kristinn P Magnusson, Gerard Tromp, James R Elmore, Natzi Sakalihasan, Raymond Limet, Jean-Olivier Defraigne, Robert E Ferrell, Antti Ronkainen, Ynte M Ruigrok, Cisca Wijmenga, Diederick E Grobbee, Svati H Shah, Christopher B Granger, Arshed A Quyyumi, Viola Vaccarino, Riyaz S Patel, A Maziar Zafari, Allan I Levey, Harland Austin, Domenico Girelli, Pier Franco Pignatti, Oliviero Olivieri, Nicola Martinelli, Giovanni Malerba, Elisabetta Trabetti, Lewis C Becker, Diane M Becker, Muredach P Reilly, Daniel J Rader, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Sigitas Urbonavicius, Bengt Lindblad, Anders Gottsäter, Eleonora Gaetani, Roberto Pola, Philip Wells, Marc Rodger, Melissa Forgie, Nicole Langlois, Javier Corral, Vicente Vicente, Jordi Fontcuberta, Francisco España, Niels Grarup, Torben Jørgensen, Daniel R Witte, Torben Hansen, Oluf Pedersen, Katja K Aben, Jacqueline de Graaf, Suzanne Holewijn, Lasse Folkersen, Anders Franco-Cereceda, Per Eriksson, David A Collier, Hreinn Stefansson, Valgerdur Steinthorsdottir, Thorunn Rafnar, Einar M Valdimarsson, Hulda B Magnadottir, Sigurlaug Sveinbjörnsdóttir, Isleifur Olafsson, Magnus Karl Magnusson, Robert Palmason, Vilhelmina Haraldsdottir, Karl Andersen, Pall T Onundarson, Gudmundur Thorgeirsson, Lambertus A Kiemeney, Janet T Powell, David J Carey, Helena Kuivaniemi, Jes S Lindholt, Gregory T Jones, Augustine Kong, Jan D Blankensteijn, Stefan E Matthiasson, Unnur Thorsteinsdottir, Kari Stefansson.
Nat. Genet.
PUBLISHED: 02-24-2010
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We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noisël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, .
Nat. Genet.
PUBLISHED: 01-19-2010
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By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U Jackson, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Anna L Gloyn, Cecilia M Lindgren, Reedik Mägi, Andrew P Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter Henneman, Harald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R B Perry, Josephine M Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F Voight, Heather M Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Felicity Payne, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Kristin Ardlie, Yavuz Ariyurek, Beverley Balkau, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Rafn Benediktsson, Amanda J Bennett, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Guillaume Charpentier, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Marilyn Cornelis, Gabe Crawford, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Christian Dina, Michael R Erdos, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Caroline S Fox, Rune Frants, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Christopher J Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, Samy Hadjadj, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Neelam Hassanali, Caroline Hayward, Simon C Heath, Serge Hercberg, Christian Herder, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Albert Hofman, Jennie Hui, Joe Hung, Bo Isomaa, Paul R V Johnson, Torben Jørgensen, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Valeriya Lyssenko, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Laura J McCulloch, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Mario A Morken, Sutapa Mukherjee, Silvia Naitza, Narisu Narisu, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Colin N A Palmer, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Wolfgang Rathmann, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Michael Roden, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Laura J Scott, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurethsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Barbara Thorand, Jean Tichet, Anke Tönjes, Tiinamaija Tuomi, André G Uitterlinden, Ko Willems van Dijk, Mandy van Hoek, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, G Bragi Walters, Kim L Ward, Hugh Watkins, Michael N Weedon, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Eleftheria Zeggini, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, , Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Andrew T Hattersley, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Andrew D Morris, Lars Lind, Lyle J Palmer, Frank B Hu, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, James S Pankow, Michael J Sampson, Johanna Kuusisto, Markku Laakso, Torben Hansen, Oluf Pedersen, Peter Paul Pramstaller, H Erich Wichmann, Thomas Illig, Igor Rudan, Alan F Wright, Michael Stumvoll, Harry Campbell, James F Wilson, Richard N Bergman, Thomas A Buchanan, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Timo T Valle, David Altshuler, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Timothy M Frayling, Luigi Ferrucci, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Cornelia M van Duijn, Yurii S Aulchenko, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Gonçalo R Abecasis, Nicholas J Wareham, Robert Sladek, Philippe Froguel, Richard M Watanabe, James B Meigs, Leif Groop, Michael Boehnke, Mark I McCarthy, Jose C Florez, Inês Barroso.
Nat. Genet.
PUBLISHED: 01-17-2010
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Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.
Richa Saxena, Marie-France Hivert, Claudia Langenberg, Toshiko Tanaka, James S Pankow, Peter Vollenweider, Valeriya Lyssenko, Nabila Bouatia-Naji, Josée Dupuis, Anne U Jackson, W H Linda Kao, Man Li, Nicole L Glazer, Alisa K Manning, Jian'an Luan, Heather M Stringham, Inga Prokopenko, Toby Johnson, Niels Grarup, Trine W Boesgaard, Cécile Lecoeur, Peter Shrader, Jeffrey O'Connell, Erik Ingelsson, David J Couper, Kenneth Rice, Kijoung Song, Camilla H Andreasen, Christian Dina, Anna Köttgen, Olivier Le Bacquer, François Pattou, Jalal Taneera, Valgerdur Steinthorsdottir, Denis Rybin, Kristin Ardlie, Michael Sampson, Lu Qi, Mandy van Hoek, Michael N Weedon, Yurii S Aulchenko, Benjamin F Voight, Harald Grallert, Beverley Balkau, Richard N Bergman, Suzette J Bielinski, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Thomas A Buchanan, Suzannah J Bumpstead, Christine Cavalcanti-Proença, Guillaume Charpentier, Yii-Der Ida Chen, Peter S Chines, Francis S Collins, Marilyn Cornelis, Gabriel J Crawford, Jérôme Delplanque, Alex Doney, Josephine M Egan, Michael R Erdos, Mathieu Firmann, Nita G Forouhi, Caroline S Fox, Mark O Goodarzi, Jurgen Graessler, Aroon Hingorani, Bo Isomaa, Torben Jørgensen, Mika Kivimäki, Peter Kovacs, Knut Krohn, Meena Kumari, Torsten Lauritzen, Claire Levy-Marchal, Vladimir Mayor, Jarred B McAteer, David Meyre, Braxton D Mitchell, Karen L Mohlke, Mario A Morken, Narisu Narisu, Colin N A Palmer, Ruth Pakyz, Laura Pascoe, Felicity Payne, Daniel Pearson, Wolfgang Rathmann, Annelli Sandbaek, Avan Aihie Sayer, Laura J Scott, Stephen J Sharp, Eric Sijbrands, Andrew Singleton, David S Siscovick, Nicholas L Smith, Thomas Sparsø, Amy J Swift, Holly Syddall, Gudmar Thorleifsson, Anke Tönjes, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T Valle, Gérard Waeber, Andrew Walley, Dawn M Waterworth, Eleftheria Zeggini, Jing Hua Zhao, , Thomas Illig, H Erich Wichmann, James F Wilson, Cornelia van Duijn, Frank B Hu, Andrew D Morris, Timothy M Frayling, Andrew T Hattersley, Unnur Thorsteinsdottir, Kari Stefansson, Peter Nilsson, Ann-Christine Syvänen, Alan R Shuldiner, Mark Walker, Stefan R Bornstein, Peter Schwarz, Gordon H Williams, David M Nathan, Johanna Kuusisto, Markku Laakso, Cyrus Cooper, Michael Marmot, Luigi Ferrucci, Vincent Mooser, Michael Stumvoll, Ruth J F Loos, David Altshuler, Bruce M Psaty, Jerome I Rotter, Eric Boerwinkle, Torben Hansen, Oluf Pedersen, Jose C Florez, Mark I McCarthy, Michael Boehnke, Inês Barroso, Robert Sladek, Philippe Froguel, James B Meigs, Leif Groop, Nicholas J Wareham, Richard M Watanabe.
Nat. Genet.
PUBLISHED: 01-17-2010
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Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
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Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.
Hum. Mol. Genet.
PUBLISHED: 11-18-2009
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Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
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Parental origin of sequence variants associated with complex diseases.
Nature
PUBLISHED: 08-14-2009
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Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
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Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche.
Nat. Genet.
PUBLISHED: 04-21-2009
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Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.
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The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects.
Hum. Mol. Genet.
PUBLISHED: 04-18-2009
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A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 x 10(-5)]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample sizes.
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Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renstrom, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gérard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, , Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Järvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy.
PLoS Genet.
PUBLISHED: 02-18-2009
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To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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New common variants affecting susceptibility to basal cell carcinoma.
Nat. Genet.
PUBLISHED: 02-03-2009
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In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
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Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.
Nat. Genet.
PUBLISHED: 01-24-2009
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Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
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Variants in MTNR1B influence fasting glucose levels.
Inga Prokopenko, Claudia Langenberg, Jose C Florez, Richa Saxena, Nicole Soranzo, Gudmar Thorleifsson, Ruth J F Loos, Alisa K Manning, Anne U Jackson, Yurii Aulchenko, Simon C Potter, Michael R Erdos, Serena Sanna, Jouke-Jan Hottenga, Eleanor Wheeler, Marika Kaakinen, Valeriya Lyssenko, Wei-Min Chen, Kourosh Ahmadi, Jacques S Beckmann, Richard N Bergman, Murielle Bochud, Lori L Bonnycastle, Thomas A Buchanan, Antonio Cao, Alessandra Cervino, Lachlan Coin, Francis S Collins, Laura Crisponi, Eco J C de Geus, Abbas Dehghan, Panos Deloukas, Alex S F Doney, Paul Elliott, Nelson Freimer, Vesela Gateva, Christian Herder, Albert Hofman, Thomas E Hughes, Sarah Hunt, Thomas Illig, Michael Inouye, Bo Isomaa, Toby Johnson, Augustine Kong, Maria Krestyaninova, Johanna Kuusisto, Markku Laakso, Noha Lim, Ulf Lindblad, Cecilia M Lindgren, Owen T McCann, Karen L Mohlke, Andrew D Morris, Silvia Naitza, Marco Orrù, Colin N A Palmer, Anneli Pouta, Joshua Randall, Wolfgang Rathmann, Jouko Saramies, Paul Scheet, Laura J Scott, Angelo Scuteri, Stephen Sharp, Eric Sijbrands, Jan H Smit, Kijoung Song, Valgerdur Steinthorsdottir, Heather M Stringham, Tiinamaija Tuomi, Jaakko Tuomilehto, André G Uitterlinden, Benjamin F Voight, Dawn Waterworth, H-Erich Wichmann, Gonneke Willemsen, Jacqueline C M Witteman, Xin Yuan, Jing Hua Zhao, Eleftheria Zeggini, David Schlessinger, Manjinder Sandhu, Dorret I Boomsma, Manuela Uda, Tim D Spector, Brenda Wjh Penninx, David Altshuler, Peter Vollenweider, Marjo Riitta Jarvelin, Edward Lakatta, Gérard Waeber, Caroline S Fox, Leena Peltonen, Leif C Groop, Vincent Mooser, L Adrienne Cupples, Unnur Thorsteinsdottir, Michael Boehnke, Inês Barroso, Cornelia van Duijn, Josée Dupuis, Richard M Watanabe, Kari Stefansson, Mark I McCarthy, Nicholas J Wareham, James B Meigs, Gonçalo R Abecasis.
Nat. Genet.
PUBLISHED: 01-24-2009
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To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.
Nat. Genet.
PUBLISHED: 01-05-2009
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Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
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FTO genotype is associated with phenotypic variability of body mass index.
Jian Yang, Ruth J F Loos, Joseph E Powell, Sarah E Medland, Elizabeth K Speliotes, Daniel I Chasman, Lynda M Rose, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Reedik Mägi, Lindsay Waite, Albert Vernon Smith, Laura M Yerges-Armstrong, Keri L Monda, David Hadley, Anubha Mahajan, Guo Li, Karen Kapur, Veronique Vitart, Jennifer E Huffman, Sophie R Wang, Cameron Palmer, Tonu Esko, Krista Fischer, Jing Hua Zhao, Ayse Demirkan, Aaron Isaacs, Mary F Feitosa, Jian'an Luan, Nancy L Heard-Costa, Charles White, Anne U Jackson, Michael Preuss, Andreas Ziegler, Joel Eriksson, Zoltan Kutalik, Francesca Frau, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Jouke-Jan Hottenga, Kevin B Jacobs, Niek Verweij, Anuj Goel, Carolina Medina-Gomez, Karol Estrada, Jennifer Lynn Bragg-Gresham, Serena Sanna, Carlo Sidore, Jonathan Tyrer, Alexander Teumer, Inga Prokopenko, Massimo Mangino, Cecilia M Lindgren, Themistocles L Assimes, Alan R Shuldiner, Jennie Hui, John P Beilby, Wendy L McArdle, Per Hall, Talin Haritunians, Lina Zgaga, Ivana Kolčić, Ozren Polašek, Tatijana Zemunik, Ben A Oostra, M Juhani Junttila, Henrik Grönberg, Stefan Schreiber, Annette Peters, Andrew A Hicks, Jonathan Stephens, Nicola S Foad, Jaana Laitinen, Anneli Pouta, Marika Kaakinen, Gonneke Willemsen, Jacqueline M Vink, Sarah H Wild, Gerjan Navis, Folkert W Asselbergs, Georg Homuth, Ulrich John, Carlos Iribarren, Tamara Harris, Lenore Launer, Vilmundur Gudnason, Jeffrey R O'Connell, Eric Boerwinkle, Gemma Cadby, Lyle J Palmer, Alan L James, Arthur W Musk, Erik Ingelsson, Bruce M Psaty, Jacques S Beckmann, Gérard Waeber, Peter Vollenweider, Caroline Hayward, Alan F Wright, Igor Rudan, Leif C Groop, Andres Metspalu, Kay Tee Khaw, Cornelia M van Duijn, Ingrid B Borecki, Michael A Province, Nicholas J Wareham, Jean-Claude Tardif, Heikki V Huikuri, L Adrienne Cupples, Larry D Atwood, Caroline S Fox, Michael Boehnke, Francis S Collins, Karen L Mohlke, Jeanette Erdmann, Heribert Schunkert, Christian Hengstenberg, Klaus Stark, Mattias Lorentzon, Claes Ohlsson, Daniele Cusi, Jan A Staessen, Melanie M van der Klauw, Peter P Pramstaller, Sekar Kathiresan, Jennifer D Jolley, Samuli Ripatti, Marjo-Riitta Järvelin, Eco J C de Geus, Dorret I Boomsma, Brenda Penninx, James F Wilson, Harry Campbell, Stephen J Chanock, Pim van der Harst, Anders Hamsten, Hugh Watkins, Albert Hofman, Jacqueline C Witteman, M Carola Zillikens, André G Uitterlinden, Fernando Rivadeneira, Lambertus A Kiemeney, Sita H Vermeulen, Gonçalo R Abecasis, David Schlessinger, Sabine Schipf, Michael Stumvoll, Anke Tönjes, Tim D Spector, Kari E North, Guillaume Lettre, Mark I McCarthy, Sonja I Berndt, Andrew C Heath, Pamela A F Madden, Dale R Nyholt, Grant W Montgomery, Nicholas G Martin, Barbara McKnight, David P Strachan, William G Hill, Harold Snieder, Paul M Ridker, Unnur Thorsteinsdottir, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn, Michael E Goddard, Peter M Visscher.
Nature
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There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ?170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ?0.5?kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Andrew P Morris, Benjamin F Voight, Tanya M Teslovich, Teresa Ferreira, Ayellet V Segrè, Valgerdur Steinthorsdottir, Rona J Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tonu Esko, Ross M Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian'an Luan, Cecilia M Lindgren, Martina Müller-Nurasyid, Sonali Pechlivanis, N William Rayner, Laura J Scott, Steven Wiltshire, Loïc Yengo, Leena Kinnunen, Elizabeth J Rossin, Soumya Raychaudhuri, Andrew D Johnson, Antigone S Dimas, Ruth J F Loos, Sailaja Vedantam, Han Chen, Jose C Florez, Caroline Fox, Ching-Ti Liu, Denis Rybin, David J Couper, Wen Hong L Kao, Man Li, Marilyn C Cornelis, Peter Kraft, Qi Sun, Rob M Van Dam, Heather M Stringham, Peter S Chines, Krista Fischer, Pierre Fontanillas, Oddgeir L Holmen, Sarah E Hunt, Anne U Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R B Perry, Carl G P Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Gudmar Thorleifsson, Emmi Tikkanen, Andrew R Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L Bonnycastle, Noel Burtt, Jason Carey, Guillaume Charpentier, Andrew T Crenshaw, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsén, Karl Gertow, Bruna Gigante, George B Grant, Christopher J Groves, Candace Guiducci, Christian Herder, Astradur B Hreidarsson, Jennie Hui, Alan James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravic, Kaarel Krjutskov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu Mannisto, Ghazala Mirza, Thomas W Mühleisen, Bill Musk, Melissa Parkin, Loukianos Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigurðsson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia van Duijn, André G Uitterlinden, Albert Hofman, Eric Sijbrands, Gonçalo R Abecasis, Katharine R Owen, Eleftheria Zeggini, Mieke D Trip, Nita G Forouhi, Ann-Christine Syvänen, Johan G Eriksson, Leena Peltonen, Markus M Nöthen, Beverley Balkau, Colin N A Palmer, Valeriya Lyssenko, Tiinamaija Tuomi, Bo Isomaa, David J Hunter, Lu Qi, , Alan R Shuldiner, Michael Roden, Inês Barroso, Tom Wilsgaard, John Beilby, Kees Hovingh, Jackie F Price, James F Wilson, Rainer Rauramaa, Timo A Lakka, Lars Lind, George Dedoussis, Inger Njølstad, Nancy L Pedersen, Kay-Tee Khaw, Nicholas J Wareham, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Eeva Korpi-Hyövälti, Juha Saltevo, Markku Laakso, Johanna Kuusisto, Andres Metspalu, Francis S Collins, Karen L Mohlke, Richard N Bergman, Jaakko Tuomilehto, Bernhard O Boehm, Christian Gieger, Kristian Hveem, Stéphane Cauchi, Philippe Froguel, Damiano Baldassarre, Elena Tremoli, Steve E Humphries, Danish Saleheen, John Danesh, Erik Ingelsson, Samuli Ripatti, Veikko Salomaa, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Annette Peters, Thomas Illig, Ulf de Faire, Anders Hamsten, Andrew D Morris, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M Nilsson, Panos Deloukas, Unnur Thorsteinsdottir, Leif C Groop, Kari Stefansson, Frank Hu, James S Pankow, Josée Dupuis, James B Meigs, David Altshuler, Michael Boehnke, Mark I McCarthy.
Nat. Genet.
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To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
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Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
PLoS Genet.
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Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m²) compared to obese cases (BMI?30 Kg/m²). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m²) or 4,123 obese cases (BMI?30 kg/m²), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P?=?8.4×10??, OR?=?1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P?=?0.04, OR?=?1.03 [95% CI 1.00-1.06]). A variant in HMG20A--previously identified in South Asians but not Europeans--was associated with type 2 diabetes in obese cases (P?=?1.3×10??, OR?=?1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P?=?0.02, OR?=?1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P?=?0.0002). In the lean analysis, we observed a weighted per-risk allele OR?=?1.13 [95% CI 1.10-1.17], P?=?3.2×10?¹?. This was larger than the same model fitted in the obese analysis where the OR?=?1.06 [95% CI 1.05-1.08], P?=?2.2×10?¹?. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
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Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, , James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josée Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noel P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Paré, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Asa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena González, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-Der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, José M Ordovás, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan.
PLoS Genet.
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Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P?=?4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N?=?4,232 African Americans, N?=?1,776 Asians, and N?=?29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p?=?4.3×10(-3), n?=?22,044), increased triglycerides (p?=?2.6×10(-14), n?=?93,440), increased waist-to-hip ratio (p?=?1.8×10(-5), n?=?77,167), increased glucose two hours post oral glucose tolerance testing (p?=?4.4×10(-3), n?=?15,234), increased fasting insulin (p?=?0.015, n?=?48,238), but with lower in HDL-cholesterol concentrations (p?=?4.5×10(-13), n?=?96,748) and decreased BMI (p?=?1.4×10(-4), n?=?121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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A genome-wide association search for type 2 diabetes genes in African Americans.
Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, , Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michèle M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noel P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek.
PLoS ONE
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African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n?=?550 independent loci) were genotyped in a replication cohort and 122 SNPs (n?=?98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P?=?7.0×10(-9), OR (95% CI)?=?0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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