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

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114 Scopus citations

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

Bibliographical note

Funding Information:
Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding for Coronary Artery Risk Development in Young Adults (CARDIA) include support to University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest School of Medicine (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California Irvine (N01-HC-45134, N01-HC-95100). Funding to Candidate-gene Association Resource (CARe) (http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx) include support to Massachusetts Institute of Technology - Broad Institute (N01-HC-65226). Cleveland Family Study (CFS) was supported by a grant to Case Western Reserve University (NIH HL 46380, M01RR00080). Cardiovascular Health Study (CHS) was supported by NHLBI contracts HL085251, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756, HL103612, and HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 rom the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHSNHLBI. org/. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124, the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Electronic Medical Records and Genomics Network (eMERGE) Network was initiated and funded by NHGRI, with additional funding from NIGMS through the following grants: U01-HG-004610 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01-HG-04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01-HG-04603 (Vanderbilt University, also serving as the Coordinating Center), and the State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Medical Genetics. The Northwestern University Enterprise Data Warehouse was funded in part by a grant from the National Center for Research Resources, UL1RR025741. The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center?s BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Family Heart Study (FamHS) was supported by NIH grants R01-HL-087700 and R01-HL-088215 (MAP, Principal Investigator) from NHLBI; and R01-DK-8925601 and R01-DK-075681 (IBB, Principal Investigator) from NIDDK. Family Investigation of Nephropathy in Diabetes (FIND) was supported by FIND grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, and U01DK070657, U01DK57304. This project has been funded in whole or in part with federal funds from the NIH National Cancer Institute (NCI) under contract N01-CO-12400 and the Intramural Research Program of the NIH-NCI Center for Cancer Research. This work also was supported by the National Center for Research Resources for the General Clinical Research Center grants: Case Western Reserve University, M01-RR-000080; Wake Forest University, M01-RR-07122; Harbor-University of California, Los Angeles Medical Center, M01-RR-00425; College of Medicine, University of California, Irvine, M01-RR-00827-29; University of New Mexico, HSC M01-RR-00997; and Frederic C. Bartter, M01-RR-01346. The CHOICE Study was supported in part by HS08365 from the Agency for Healthcare Research and Quality, Rockville, MD, and HL62985 from the National Heart, Lung, and Blood Institute, Bethesda, MD. Genetic Study of Atherosclerosis Risk (GeneSTAR) was supported by NIH grants through the National Heart, Lung, and Blood Institute (HL58625-01A1, HL59684, HL071025-01A1, U01HL72518, and HL087698) and the National Institute of Nursing Research (NR0224103) and by M01-RR000052 to the Johns Hopkins General Clinical Research Center. Genetic Epidemiology Network of Arteriopathy (GENOA) study is supported by the National Institutes of Health grant numbers HL087660, HL100245 and HL100185 from the National Heart, Lung, and Blood Institute. Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS) was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (project # Z01-AG000513 and human subjects protocol # 2009-149). Health, Aging, and Body Composition Study (Health ABC Study) was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Howard University Family Study (HUFS) was supported by National Institutes of Health grants S06GM008016-320107 to CNR and S06GM008016- 380111 to AA. Participant enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. Genotyping support was provided by the Coriell Institute for Medical Research. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). The Charles Bronfman Institute for Personalized Medicine (IPM) BioBank Program is supported by The Andrea and Charles Bronfman Philanthropies. Insulin Resistance Atherosclerosis Study (IRAS) was supported by the National Heart, Lung, and Blood Institute (HL047887, HL047889, HL047890, HL47902). IRAS Family Study was supported by the National Heart, Lung, and Blood Institute (HL060944, HL060894, HL061210). The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA), MESA Family, and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and UL1-RR-024156. Funding for MESA Family is provided by grants R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, and UL1-RR-025005. Funding for genotyping was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226. MESA Air is funded by the US EPA - Science to Achieve Results (STAR)Program Grant #RD831697. The project described was supported by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124. In Southern Community Cohort Study (SCCS), sample preparation was conducted at the Survey and Biospecimen Shared Resources, which is supported in part by Vanderbilt- Ingram Cancer Center (P30 CA68485). The SCCS dataset used for the present analyses was supported by U.S. NIH grant R01CA92447. In Sea Islands Genetic Network (SIGNET) - Reasons for Geographic And Racial Differences in Stroke (SIGNET-REGARDS), the REGARDS Study is supported by a cooperative agreement U01 NS041588 (PI George Howard) and SIGNET was supported by R01 DK084350 (MMS) from the National Institutes of Health. In Wake Forest School of Medicine (WFSM), genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. The work at Wake Forest was supported by NIH grants K99 DK081350 (NDP), R01 DK066358 (DWB), R01 DK053591 (DWB), R01 HL56266 (BIF), R01 DK070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest School of Medicine grant M01 RR07122. Women?s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01-WH-22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. BHC was funded by the Burroughs Wellcome Fund Inter-school Training Program in Metabolic Diseases and UCLA Genomic Analysis Training Program (NHGRI T32-HG002536). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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