Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

Maggie C Y Ng, Daniel Shriner, Brian H. Chen, Jiang Li, Wei Min Chen, Xiuqing Guo, Jiankang Liu, Suzette J. Bielinski, Lisa R. Yanek, Michael A. Nalls, Mary E. Comeau, Laura J. Rasmussen-Torvik, Richard A. Jensen, Daniel S. Evans, Yan V. Sun, Ping An, Sanjay R. Patel, Yingchang Lu, Jirong Long, Loren L. ArmstrongLynne Wagenknecht, Lingyao Yang, Beverly M. Snively, Nicholette D. Palmer, Poorva Mudgal, Carl D. Langefeld, Keith L. Keene, Barry I. Freedman, Josyf C. Mychaleckyj, Uma Nayak, Leslie J. Raffel, Mark O. Goodarzi, Y. D Ida Chen, Herman A. Taylor, Adolfo Correa, Mario Sims, David Couper, James S. Pankow, Eric Boerwinkle, Adebowale Adeyemo, Ayo Doumatey, Guanjie Chen, Rasika A. Mathias, Dhananjay Vaidya, Andrew B. Singleton, Alan B. Zonderman, Robert P. Igo, John R. Sedor, Krina T. Zondervan, Edmond K. Kabagambe, David S. Siscovick, Barbara McKnight, Kenneth Rice, Yongmei Liu, Wen Chi Hsueh, Wei Zhao, Lawrence F. Bielak, Aldi Kraja, Michael A. Province, Erwin P. Bottinger, Omri Gottesman, Qiuyin Cai, Wei Zheng, William J. Blot, William L. Lowe, Jennifer A. Pacheco, Dana C. Crawford, Tsun Po Yang, Alicja Wilk, Elin Grundberg, Sophia Tsoka, Stephen S. Rich, M. Geoffrey Hayes, Xiao Ou Shu, Ruth J F Loos, Ingrid B. Borecki, Patricia A. Peyser, Steven R. Cummings, Bruce M. Psaty, Myriam Fornage, Sudha K. Iyengar, Michele K. Evans, Diane M. Becker, W. H Linda Kao, James G. Wilson, Jerome I. Rotter, Michèle M. Sale, Simin Liu, Charles N. Rotimi, Donald W. Bowden, R. C. Elston, S. Iyengar, K. Goddard, J. Olson, S. Ialacci, S. Edwards, C. Fondran, A. Horvath, G. Jun, K. Kramp, M. Slaughter, E. Zaletel, J. R. Sedor, J. Schelling, A. Sehgal, A. Pickens, L. Humbert, L. Getz-Fradley, S. Adler, H. E. Collins-Schramm, E. Ipp, H. Li1, M. Pahl, M. F. Seldin, J. LaPage, B. Walker, C. Garcia, J. Gonzalez, L. Ingram-Drake, M. Klag, J. Coresh, L. Kao, L. Mead, R. Parekh, N. Fink, P. Bayton, Y. Long, L. Wei, T. Whitehead, W. C. Knowler, R. L. Hanson, R. G. Nelson, L. Jones, R. Juan, R. Lovelace, C. Luethe, L. M. Phillips, J. Sewemaenewa, I. Sili, B. Waseta, M. F. Saad, X. Guo, J. Rotter, K. Taylor, M. Budgett, P. Zager, V. Shah, M. Scavini, A. Bobelu, H. Abboud, N. Arar, R. Duggirala, B. S. Kasinath, R. Plaetke, M. Stem, C. Goyes, V. Sartorio, B. I. Freedman, D. W. Bowden, S. C. Satko, S. S. Rich, S. Warren, S. Viverette, G. Brooks, R. Young, C. Winkler, M. W. Smith, M. Thompson, R. Hanson, J. P. Briggs, P. L. Kimmel, R. Rasooly, D. Warnock, R. Chakraborty, G. M. Dunston, R. P. Lifton, S. J. O’Brien, R. Spielman, Catherine A. McCarty, Justin Starren, Peggy Peissig, Richard Berg, Luke Rasmussen, James Linneman, Aaron Miller, Vidhu Choudary, Lin Chen, Carol Waudby, Terrie Kitchner, Jonathan Reeser, Norman Fost, Marylyn Ritchie, Russell A. Wilke, Rex L. Chisholm, Pedro C. Avila, Philip Greenland, M. Geoffrey Hayes, Abel N. Kho, Warren A. Kibbe, Amy A. Lemke, William L. Lowe, Maureen E. Smith, Wendy A. Wolf, Jennifer A. Pacheco, William K. Thompson, Joel Humowiecki, May Law, Laura Rasmussen-Torvik, Christopher Chute, Iftikar Kullo, Barbara Koenig, Mariza de Andrade, Suzette Bielinski, Jyotishman Pathak, Guergana Savova, Joel Wu, Joan Henriksen, Keyue Ding, Lacey Hart, Jeremy Palbicki, Eric B. Larson, Katherine Newton, Evette Ludman, Leslie Spangler, Gene Hart, David Carrell, Gail Jarvik, Paul Crane, Wylie Burke, Stephanie Malia Fullerton, Susan Brown Trinidad, Chris Carlson, Andrew McDavid, Dan M. Roden, Ellen Clayton, Jonathan L. Haines, Daniel R. Masys, Larry R. Churchill, Daniel Cornfield, Dana Crawford, Dawood Darbar, Joshua C. Denny, Bradley A. Malin, Marylyn D. Ritchie, Jonathan S. Schildcrout, Hua Xu, Andrea Havens Ramirez, Melissa Basford, Jill Pulley, 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, Loukia Tsaprouni, Mary E. Travers, Richard N. Bergman, Stephane 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, Andre 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, 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, Kourosh R. Ahmadi, Chrysanthi Ainali, Amy Barrett, Veronique Bataille, Jordana T. Bell, Alfonso Buil, Panos Deloukas, Emmanouil T. Dermitzakis, Antigone S. Dimas, Richard Durbin, Daniel Glass, Elin Grundberg, Neelam Hassanali, Åsa K. Hedman, Catherine Ingle, David Knowles, Maria Krestyaninova, Cecilia M. Lindgren, Christopher E. Lowe, Mark I. McCarthy, Eshwar Meduri, Paola di Meglio, Josine L. Min, Stephen B. Montgomery, Frank O. Nestle, Alexandra C. Nica, James Nisbet, Stephen O’Rahilly, Leopold Parts, Simon Potter, Magdalena Sekowska, So Youn Shin, Kerrin S. Small, Nicole Soranzo, Tim D. Spector, Gabriela Surdulescu

Research output: Contribution to journalArticle

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Abstract

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94<P<5×10−8, odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2×10−23 < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

Original languageEnglish (US)
Article numbere1004517
JournalPLoS genetics
Volume10
Issue number8
DOIs
StatePublished - Aug 7 2014

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    Ng, M. C. Y., Shriner, D., Chen, B. H., Li, J., Chen, W. M., Guo, X., Liu, J., Bielinski, S. J., Yanek, L. R., Nalls, M. A., Comeau, M. E., Rasmussen-Torvik, L. J., Jensen, R. A., Evans, D. S., Sun, Y. V., An, P., Patel, S. R., Lu, Y., Long, J., ... Surdulescu, G. (2014). Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes. PLoS genetics, 10(8), [e1004517]. https://doi.org/10.1371/journal.pgen.1004517