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

The MAGIC investigators; The GIANT consortium

doi:10.1371/journal.pgen.1004517

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

The MAGIC investigators, The GIANT consortium

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 language	English
Article number	e1004517
Journal	PLoS Genetics
Volume	10
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1004517
Publication status	Published - 7 Aug 2014

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10.1371/journal.pgen.1004517

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@article{68dac61e778d41869a3de1cba4a350c0,

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

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.",

author = "{The MAGIC investigators} and {The GIANT consortium} and Ng, {Maggie C.Y.} and Daniel Shriner and Chen, {Brian H.} and Jiang Li and Chen, {Wei Min} and Xiuqing Guo and Jiankang Liu and Bielinski, {Suzette J.} and Yanek, {Lisa R.} and Nalls, {Michael A.} and Comeau, {Mary E.} and Rasmussen-Torvik, {Laura J.} and Jensen, {Richard A.} and Evans, {Daniel S.} and Sun, {Yan V.} and Ping An and Patel, {Sanjay R.} and Yingchang Lu and Jirong Long and Armstrong, {Loren L.} and Lynne Wagenknecht and Lingyao Yang and Snively, {Beverly M.} and Palmer, {Nicholette D.} and Poorva Mudgal and Langefeld, {Carl D.} and Keene, {Keith L.} and Freedman, {Barry I.} and Mychaleckyj, {Josyf C.} and Uma Nayak and Raffel, {Leslie J.} and Goodarzi, {Mark O.} and Chen, {Y. D.Ida} and Taylor, {Herman A.} and Adolfo Correa and Mario Sims and Couper, {David J.} and Palmer, {Colin N.A.} and Eric Boerwinkle and Adebowale Adeyemo and Ayo Doumatey and Guanjie Chen and Mathias, {Rasika A.} and Dhananjay Vaidya and Singleton, {Andrew B.} and Zonderman, {Alan B.} and Igo, {Robert P.} and Sedor, {John R.} and Zondervan, {Krina T.} and Kabagambe, {Edmond K.} and Siscovick, {David S.} and Barbara McKnight and Kenneth Rice and Yongmei Liu and Hsueh, {Wen Chi} and Wei Zhao and Bielak, {Lawrence F.} and Aldi Kraja and Province, {Michael A.} and Bottinger, {Erwin P.} and Omri Gottesman and Qiuyin Cai and Wei Zheng and Blot, {William J.} and Lowe, {William L.} and Pacheco, {Jennifer A.} and Crawford, {Dana C.} and Yang, {Tsun Po} and Alicja Wilk and Elin Grundberg and Sophia Tsoka and Rich, {Stephen S.} and Hayes, {M. Geoffrey} and Shu, {Xiao Ou} and Loos, {Ruth J.F.} and Borecki, {Ingrid B.} and Peyser, {Patricia A.} and Cummings, {Steven R.} and Psaty, {Bruce M.} and Myriam Fornage and Iyengar, {Sudha K.} and Evans, {Michele K.} and Becker, {Diane M.} and Kao, {W. H.Linda} and Wilson, {James F.} and Rotter, {Jerome I.} and Sale, {Mich{\`e}le M.} and Simin Liu and Rotimi, {Charles N.} and Bowden, {Donald W.} and Elston, {R. C.} and K. Goddard and J. Olson and S. Ialacci and S. Edwards and C. Fondran and A. Horvath and G. Jun and K. Kramp and M. Slaughter and E. Zaletel and J. Schelling and A. Sehgal and A. Pickens and L. Humbert and L. Getz-Fradley and S. Adler and Collins-Schramm, {H. E.} and E. Ipp and H. Li1 and M. Pahl and Seldin, {M. F.} and J. LaPage and B. Walker and C. Garcia and J. Gonzalez and L. Ingram-Drake and M. Klag and J. Coresh and L. Mead and R. Parekh and N. Fink and P. Bayton and Y. Long and L. Wei and T. Whitehead and Knowler, {W. C.} and Hanson, {R. L.} and Nelson, {R. G.} and L. Jones and R. Juan and R. Lovelace and C. Luethe and Phillips, {L. M.} and J. Sewemaenewa and I. Sili and B. Waseta and Saad, {M. F.} and K. Taylor and M. Budgett and P. Zager and V. Shah and M. Scavini and A. Bobelu and H. Abboud and N. Arar and R. Duggirala and Kasinath, {B. S.} and R. Plaetke and M. Stem and C. Goyes and V. Sartorio and Satko, {S. C.} and S. Warren and S. Viverette and G. Brooks and R. Young and C. Winkler and Smith, {M. W.} and M. Thompson and Briggs, {J. P.} and Kimmel, {P. L.} and R. Rasooly and D. Warnock and R. Chakraborty and Dunston, {G. M.} and Lifton, {R. P.} and O{\textquoteright}Brien, {S. J.} and R. Spielman and McCarty, {Catherine A.} and Justin Starren and Peggy Peissig and Richard Berg and Luke Rasmussen and James Linneman and Aaron Miller and Vidhu Choudary and Lin Chen and Carol Waudby and Terrie Kitchner and Jonathan Reeser and Norman Fost and Ritchie, {Marylyn D.} and Wilke, {Russell A.} and Chisholm, {Rex L.} and Avila, {Pedro C.} and Philip Greenland and {Geoffrey Hayes}, M. and Kho, {Abel N.} and Kibbe, {Warren A.} and Lemke, {Amy A.} and Smith, {Maureen E.} and Wolf, {Wendy A.} and Thompson, {William K.} and Joel Humowiecki and May Law and Christopher Chute and Iftikar Kullo and Barbara Koenig and {de Andrade}, Mariza and Jyotishman Pathak and Guergana Savova and Joel Wu and Joan Henriksen and Keyue Ding and Lacey Hart and Jeremy Palbicki and Larson, {Eric B.} and Katherine Newton and Evette Ludman and Leslie Spangler and Gene Hart and David Carrell and Gail Jarvik and Paul Crane and Wylie Burke and {Malia Fullerton}, Stephanie and {Brown Trinidad}, Susan and Chris Carlson and Andrew McDavid and Roden, {Dan M.} and Ellen Clayton and Haines, {Jonathan L.} and Masys, {Daniel R.} and Churchill, {Larry R.} and Daniel Cornfield and Dawood Darbar and Denny, {Joshua C.} and Malin, {Bradley A.} and Schildcrout, {Jonathan S.} and Hua Xu and {Havens Ramirez}, Andrea and Melissa Basford and Jill Pulley and Voight, {Benjamin F.} and Scott, {Laura J.} and Valgerdur Steinthorsdottir and Morris, {Andrew D.} and Christian Dina and Welch, {Ryan P.} and Eleftheria Zeggini and Cornelia Huth and Aulchenko, {Yurii S.} and Gudmar Thorleifsson and Mcculloch, {Laura J.} and Teresa Ferreira and Harald Grallert and Jos{\'e}e Dupuis and Guanming Wu and Willer, {Cristen J.} and Soumya Raychaudhuri and Mccarroll, {Steve A.} and Hofmann, {Oliver M.} and Jos{\'e}e Dupuis and Lu Qi and Segr{\`e}, {Ayellet V.} and {van Hoek}, Mandy and Pau Navarro and Kristin Ardlie and Beverley Balkau and Rafn Benediktsson and Bennett, {Amanda J.} and Roza Blagieva and Bonnycastle, {Lori L.} and {Bengtsson Bostr{\"o}m}, Kristina and Bert Bravenboer and Suzannah Bumpstead and Burtt, {Nois{\"e}l P.} and Guillaume Charpentier and Chines, {Peter S.} and Marilyn Cornelis and Couper, {David J.} and Gabe Crawford and Doney, {Alex S.F.} and Elliott, {Katherine S.} and Elliott, {Amanda L.} and Erdos, {Michael R.} and Fox, {Caroline S.} and Franklin, {Christopher S.} and Martha Ganser and Christian Gieger and Niels Grarup and Todd Green and Simon Griffin and Groves, {Christopher J.} and Candace Guiducci and Samy Hadjadj and Neelam Hassanali and Christian Herder and Bo Isomaa and Jackson, {Anne U.} and Johnson, {Paul R.V.} and Torben J{\o}rgensen and Norman Klopp and Augustine Kong and Peter Kraft and Johanna Kuusisto and Torsten Lauritzen and Man Li and Aloysius Lieverse and Lindgren, {Cecilia M.} and Valeriya Lyssenko and Michel Marre and Richa Saxena and Kristian Midthjell and Morken, {Mario A.} and Narisu Narisu and Peter Nilsson and Owen, {Katharine R.} and Felicity Payne and Perry, {John R.B.} and Petersen, {Ann Kristin} and Carl Platou and Christine Proen{\c c}a and Inga Prokopenko and Wolfgang Rathmann and Rayner, {N. William} and Robertson, {Neil R.} and Ghislain Rocheleau and Michael Roden and Sampson, {Michael J.} and Richa Saxena and Shields, {Beverley M.} and Peter Shrader and Gunnar Sigurdsson and Thomas Spars{\o} and Klaus Strassburger and Stringham, {Heather M.} and Qi Sun and Swift, {Amy J.} and Barbara Thorand and Jean Tichet and Tiinamaija Tuomi and {van Dam}, {Rob M.} and {van Haeften}, {Timon W.} and {van Herpt}, Thijs and {van Vliet-Ostaptchouk}, {Jana V.} and Walters, {G. Bragi} and Weedon, {Michael N.} and Cisca Wijmenga and Jacqueline Witteman and Loukia Tsaprouni and Travers, {Mary E.} and Bergman, {Richard N.} and Stephane Cauchi and Collins, {Francis S.} and Gloyn, {Anna L.} and Ulf Gyllensten and Torben Hansen and Hide, {Winston A.} and Hitman, {Graham A.} and Albert Hofman and Hunter, {David J.} and Kristian Hveem and Markku Laakso and Mohlke, {Karen L.} and Morris, {Andrew D.} and Palmer, {Colin N.A.} and Pramstaller, {Peter P.} and Igor Rudan and Florez, {Jose C.} and Stein, {Lincoln D.} and Jaakko Tuomilehto and Andre Uitterlinden and Mark Walker and Wareham, {Nicholas J.} and Watanabe, {Richard M.} and Abecasis, {Gon{\c c}alo R.} and Boehm, {Bernhard O.} and Harry Campbell and Daly, {Mark J.} and Hattersley, {Andrew T.} and Hu, {Frank B.} and Meigs, {James B.} and Oluf Pedersen and Wichmann, {H. Erich} and In{\^e}s Barroso and Florez, {Jose C.} and Frayling, {Timothy M.} and Leif Groop and Rob Sladek and Unnur Thorsteinsdottir and Wilson, {James F.} and Thomas Illig and Philippe Froguel and {van duijn}, {Cornelia M.} and Kari Stefansson and David Altshuler and Michael Boehnke and Ahmadi, {Kourosh R.} and Chrysanthi Ainali and Amy Barrett and Veronique Bataille and Bell, {Jordana T.} and Alfonso Buil and Panos Deloukas and Dermitzakis, {Emmanouil T.} and Dimas, {Antigone S.} and Richard Durbin and Daniel Glass and Hedman, {{\AA}sa K.} and Catherine Ingle and David Knowles and Maria Krestyaninova and Lowe, {Christopher E.} and Mccarthy, {Mark I.} and Eshwar Meduri and {di Meglio}, Paola and Min, {Josine L.} and Montgomery, {Stephen B.} and Nestle, {Frank O.} and Nica, {Alexandra C.} and James Nisbet and Stephen O{\textquoteright}Rahilly and Leopold Parts and Simon Potter and Magdalena Sekowska and Shin, {So Youn} and Small, {Kerrin S.} and Nicole Soranzo and Spector, {Tim D.} and Gabriela Surdulescu",

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. Publisher Copyright: {\textcopyright} 2014.",

year = "2014",

month = aug,

day = "7",

doi = "10.1371/journal.pgen.1004517",

language = "English",

volume = "10",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "8",

}

TY - JOUR

T1 - Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

AU - The MAGIC investigators

AU - The GIANT consortium

AU - Ng, Maggie C.Y.

AU - Shriner, Daniel

AU - Chen, Brian H.

AU - Li, Jiang

AU - Chen, Wei Min

AU - Guo, Xiuqing

AU - Liu, Jiankang

AU - Bielinski, Suzette J.

AU - Yanek, Lisa R.

AU - Nalls, Michael A.

AU - Comeau, Mary E.

AU - Rasmussen-Torvik, Laura J.

AU - Jensen, Richard A.

AU - Evans, Daniel S.

AU - Sun, Yan V.

AU - An, Ping

AU - Patel, Sanjay R.

AU - Lu, Yingchang

AU - Long, Jirong

AU - Armstrong, Loren L.

AU - Wagenknecht, Lynne

AU - Yang, Lingyao

AU - Snively, Beverly M.

AU - Palmer, Nicholette D.

AU - Mudgal, Poorva

AU - Langefeld, Carl D.

AU - Keene, Keith L.

AU - Freedman, Barry I.

AU - Mychaleckyj, Josyf C.

AU - Nayak, Uma

AU - Raffel, Leslie J.

AU - Goodarzi, Mark O.

AU - Chen, Y. D.Ida

AU - Taylor, Herman A.

AU - Correa, Adolfo

AU - Sims, Mario

AU - Couper, David J.

AU - Palmer, Colin N.A.

AU - Boerwinkle, Eric

AU - Adeyemo, Adebowale

AU - Doumatey, Ayo

AU - Chen, Guanjie

AU - Mathias, Rasika A.

AU - Vaidya, Dhananjay

AU - Singleton, Andrew B.

AU - Zonderman, Alan B.

AU - Igo, Robert P.

AU - Sedor, John R.

AU - Zondervan, Krina T.

AU - Kabagambe, Edmond K.

AU - Siscovick, David S.

AU - McKnight, Barbara

AU - Rice, Kenneth

AU - Liu, Yongmei

AU - Hsueh, Wen Chi

AU - Zhao, Wei

AU - Bielak, Lawrence F.

AU - Kraja, Aldi

AU - Province, Michael A.

AU - Bottinger, Erwin P.

AU - Gottesman, Omri

AU - Cai, Qiuyin

AU - Zheng, Wei

AU - Blot, William J.

AU - Lowe, William L.

AU - Pacheco, Jennifer A.

AU - Crawford, Dana C.

AU - Yang, Tsun Po

AU - Wilk, Alicja

AU - Grundberg, Elin

AU - Tsoka, Sophia

AU - Rich, Stephen S.

AU - Hayes, M. Geoffrey

AU - Shu, Xiao Ou

AU - Loos, Ruth J.F.

AU - Borecki, Ingrid B.

AU - Peyser, Patricia A.

AU - Cummings, Steven R.

AU - Psaty, Bruce M.

AU - Fornage, Myriam

AU - Iyengar, Sudha K.

AU - Evans, Michele K.

AU - Becker, Diane M.

AU - Kao, W. H.Linda

AU - Wilson, James F.

AU - Rotter, Jerome I.

AU - Sale, Michèle M.

AU - Liu, Simin

AU - Rotimi, Charles N.

AU - Bowden, Donald W.

AU - Elston, R. C.

AU - Goddard, K.

AU - Olson, J.

AU - Ialacci, S.

AU - Edwards, S.

AU - Fondran, C.

AU - Horvath, A.

AU - Jun, G.

AU - Kramp, K.

AU - Slaughter, M.

AU - Zaletel, E.

AU - Schelling, J.

AU - Sehgal, A.

AU - Pickens, A.

AU - Humbert, L.

AU - Getz-Fradley, L.

AU - Adler, S.

AU - Collins-Schramm, H. E.

AU - Ipp, E.

AU - Li1, H.

AU - Pahl, M.

AU - Seldin, M. F.

AU - LaPage, J.

AU - Walker, B.

AU - Garcia, C.

AU - Gonzalez, J.

AU - Ingram-Drake, L.

AU - Klag, M.

AU - Coresh, J.

AU - Mead, L.

AU - Parekh, R.

AU - Fink, N.

AU - Bayton, P.

AU - Long, Y.

AU - Wei, L.

AU - Whitehead, T.

AU - Knowler, W. C.

AU - Hanson, R. L.

AU - Nelson, R. G.

AU - Jones, L.

AU - Juan, R.

AU - Lovelace, R.

AU - Luethe, C.

AU - Phillips, L. M.

AU - Sewemaenewa, J.

AU - Sili, I.

AU - Waseta, B.

AU - Saad, M. F.

AU - Taylor, K.

AU - Budgett, M.

AU - Zager, P.

AU - Shah, V.

AU - Scavini, M.

AU - Bobelu, A.

AU - Abboud, H.

AU - Arar, N.

AU - Duggirala, R.

AU - Kasinath, B. S.

AU - Plaetke, R.

AU - Stem, M.

AU - Goyes, C.

AU - Sartorio, V.

AU - Satko, S. C.

AU - Warren, S.

AU - Viverette, S.

AU - Brooks, G.

AU - Young, R.

AU - Winkler, C.

AU - Smith, M. W.

AU - Thompson, M.

AU - Briggs, J. P.

AU - Kimmel, P. L.

AU - Rasooly, R.

AU - Warnock, D.

AU - Chakraborty, R.

AU - Dunston, G. M.

AU - Lifton, R. P.

AU - O’Brien, S. J.

AU - Spielman, R.

AU - McCarty, Catherine A.

AU - Starren, Justin

AU - Peissig, Peggy

AU - Berg, Richard

AU - Rasmussen, Luke

AU - Linneman, James

AU - Miller, Aaron

AU - Choudary, Vidhu

AU - Chen, Lin

AU - Waudby, Carol

AU - Kitchner, Terrie

AU - Reeser, Jonathan

AU - Fost, Norman

AU - Ritchie, Marylyn D.

AU - Wilke, Russell A.

AU - Chisholm, Rex L.

AU - Avila, Pedro C.

AU - Greenland, Philip

AU - Geoffrey Hayes, M.

AU - Kho, Abel N.

AU - Kibbe, Warren A.

AU - Lemke, Amy A.

AU - Smith, Maureen E.

AU - Wolf, Wendy A.

AU - Thompson, William K.

AU - Humowiecki, Joel

AU - Law, May

AU - Chute, Christopher

AU - Kullo, Iftikar

AU - Koenig, Barbara

AU - de Andrade, Mariza

AU - Pathak, Jyotishman

AU - Savova, Guergana

AU - Wu, Joel

AU - Henriksen, Joan

AU - Ding, Keyue

AU - Hart, Lacey

AU - Palbicki, Jeremy

AU - Larson, Eric B.

AU - Newton, Katherine

AU - Ludman, Evette

AU - Spangler, Leslie

AU - Hart, Gene

AU - Carrell, David

AU - Jarvik, Gail

AU - Crane, Paul

AU - Burke, Wylie

AU - Malia Fullerton, Stephanie

AU - Brown Trinidad, Susan

AU - Carlson, Chris

AU - McDavid, Andrew

AU - Roden, Dan M.

AU - Clayton, Ellen

AU - Haines, Jonathan L.

AU - Masys, Daniel R.

AU - Churchill, Larry R.

AU - Cornfield, Daniel

AU - Darbar, Dawood

AU - Denny, Joshua C.

AU - Malin, Bradley A.

AU - Schildcrout, Jonathan S.

AU - Xu, Hua

AU - Havens Ramirez, Andrea

AU - Basford, Melissa

AU - Pulley, Jill

AU - Voight, Benjamin F.

AU - Scott, Laura J.

AU - Steinthorsdottir, Valgerdur

AU - Morris, Andrew D.

AU - Dina, Christian

AU - Welch, Ryan P.

AU - Zeggini, Eleftheria

AU - Huth, Cornelia

AU - Aulchenko, Yurii S.

AU - Thorleifsson, Gudmar

AU - Mcculloch, Laura J.

AU - Ferreira, Teresa

AU - Grallert, Harald

AU - Dupuis, Josée

AU - Wu, Guanming

AU - Willer, Cristen J.

AU - Raychaudhuri, Soumya

AU - Mccarroll, Steve A.

AU - Hofmann, Oliver M.

AU - Dupuis, Josée

AU - Qi, Lu

AU - Segrè, Ayellet V.

AU - van Hoek, Mandy

AU - Navarro, Pau

AU - Ardlie, Kristin

AU - Balkau, Beverley

AU - Benediktsson, Rafn

AU - Bennett, Amanda J.

AU - Blagieva, Roza

AU - Bonnycastle, Lori L.

AU - Bengtsson Boström, Kristina

AU - Bravenboer, Bert

AU - Bumpstead, Suzannah

AU - Burtt, Noisël P.

AU - Charpentier, Guillaume

AU - Chines, Peter S.

AU - Cornelis, Marilyn

AU - Couper, David J.

AU - Crawford, Gabe

AU - Doney, Alex S.F.

AU - Elliott, Katherine S.

AU - Elliott, Amanda L.

AU - Erdos, Michael R.

AU - Fox, Caroline S.

AU - Franklin, Christopher S.

AU - Ganser, Martha

AU - Gieger, Christian

AU - Grarup, Niels

AU - Green, Todd

AU - Griffin, Simon

AU - Groves, Christopher J.

AU - Guiducci, Candace

AU - Hadjadj, Samy

AU - Hassanali, Neelam

AU - Herder, Christian

AU - Isomaa, Bo

AU - Jackson, Anne U.

AU - Johnson, Paul R.V.

AU - Jørgensen, Torben

AU - Klopp, Norman

AU - Kong, Augustine

AU - Kraft, Peter

AU - Kuusisto, Johanna

AU - Lauritzen, Torsten

AU - Li, Man

AU - Lieverse, Aloysius

AU - Lindgren, Cecilia M.

AU - Lyssenko, Valeriya

AU - Marre, Michel

AU - Saxena, Richa

AU - Midthjell, Kristian

AU - Morken, Mario A.

AU - Narisu, Narisu

AU - Nilsson, Peter

AU - Owen, Katharine R.

AU - Payne, Felicity

AU - Perry, John R.B.

AU - Petersen, Ann Kristin

AU - Platou, Carl

AU - Proença, Christine

AU - Prokopenko, Inga

AU - Rathmann, Wolfgang

AU - Rayner, N. William

AU - Robertson, Neil R.

AU - Rocheleau, Ghislain

AU - Roden, Michael

AU - Sampson, Michael J.

AU - Saxena, Richa

AU - Shields, Beverley M.

AU - Shrader, Peter

AU - Sigurdsson, Gunnar

AU - Sparsø, Thomas

AU - Strassburger, Klaus

AU - Stringham, Heather M.

AU - Sun, Qi

AU - Swift, Amy J.

AU - Thorand, Barbara

AU - Tichet, Jean

AU - Tuomi, Tiinamaija

AU - van Dam, Rob M.

AU - van Haeften, Timon W.

AU - van Herpt, Thijs

AU - van Vliet-Ostaptchouk, Jana V.

AU - Walters, G. Bragi

AU - Weedon, Michael N.

AU - Wijmenga, Cisca

AU - Witteman, Jacqueline

AU - Tsaprouni, Loukia

AU - Travers, Mary E.

AU - Bergman, Richard N.

AU - Cauchi, Stephane

AU - Collins, Francis S.

AU - Gloyn, Anna L.

AU - Gyllensten, Ulf

AU - Hansen, Torben

AU - Hide, Winston A.

AU - Hitman, Graham A.

AU - Hofman, Albert

AU - Hunter, David J.

AU - Hveem, Kristian

AU - Laakso, Markku

AU - Mohlke, Karen L.

AU - Morris, Andrew D.

AU - Palmer, Colin N.A.

AU - Pramstaller, Peter P.

AU - Rudan, Igor

AU - Florez, Jose C.

AU - Stein, Lincoln D.

AU - Tuomilehto, Jaakko

AU - Uitterlinden, Andre

AU - Walker, Mark

AU - Wareham, Nicholas J.

AU - Watanabe, Richard M.

AU - Abecasis, Gonçalo R.

AU - Boehm, Bernhard O.

AU - Campbell, Harry

AU - Daly, Mark J.

AU - Hattersley, Andrew T.

AU - Hu, Frank B.

AU - Meigs, James B.

AU - Pedersen, Oluf

AU - Wichmann, H. Erich

AU - Barroso, Inês

AU - Florez, Jose C.

AU - Frayling, Timothy M.

AU - Groop, Leif

AU - Sladek, Rob

AU - Thorsteinsdottir, Unnur

AU - Wilson, James F.

AU - Illig, Thomas

AU - Froguel, Philippe

AU - van duijn, Cornelia M.

AU - Stefansson, Kari

AU - Altshuler, David

AU - Boehnke, Michael

AU - Ahmadi, Kourosh R.

AU - Ainali, Chrysanthi

AU - Barrett, Amy

AU - Bataille, Veronique

AU - Bell, Jordana T.

AU - Buil, Alfonso

AU - Deloukas, Panos

AU - Dermitzakis, Emmanouil T.

AU - Dimas, Antigone S.

AU - Durbin, Richard

AU - Glass, Daniel

AU - Hedman, Åsa K.

AU - Ingle, Catherine

AU - Knowles, David

AU - Krestyaninova, Maria

AU - Lowe, Christopher E.

AU - Mccarthy, Mark I.

AU - Meduri, Eshwar

AU - di Meglio, Paola

AU - Min, Josine L.

AU - Montgomery, Stephen B.

AU - Nestle, Frank O.

AU - Nica, Alexandra C.

AU - Nisbet, James

AU - O’Rahilly, Stephen

AU - Parts, Leopold

AU - Potter, Simon

AU - Sekowska, Magdalena

AU - Shin, So Youn

AU - Small, Kerrin S.

AU - Soranzo, Nicole

AU - Spector, Tim D.

AU - Surdulescu, Gabriela

N1 - 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. Publisher Copyright: © 2014.

PY - 2014/8/7

Y1 - 2014/8/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84946031456&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1004517

DO - 10.1371/journal.pgen.1004517

M3 - Article

C2 - 25102180

AN - SCOPUS:84946031456

SN - 1553-7390

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

IS - 8

M1 - e1004517

ER -

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

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