Introduction

The prevalence of type 2 diabetes (T2D) among adults in the USA is currently 11.3%, with substantially higher prevalence in African Americans (18.7%) than in European Americans (10.2%) [1]. To date, genome-wide association studies (GWAS) have identified >70 susceptibility loci for T2D [2]–[8]. While it is known that T2D is heritable in African Americans [9], it is unclear how much heritability is explained by the known genetic associations discovered primarily from European ancestry populations and whether there are risk loci specific to African Americans. Given that individuals of African ancestry tend to harbor more genetic diversity than individuals of other ancestries [10], we hypothesized that large-scale association analyses in African Americans could shed light on the genetic architecture of T2D and the risk attributable to cosmopolitan vs. population-specific variants.

Results

T2D loci reaching genome-wide significance

Five independent loci reached genome-wide significance (P<5×10⁻⁸). Stage 1 meta-analysis identified the established TCF7L2 locus. Stage 1+2a meta-analysis identified the established KCNQ1 and HMGA2 loci. Stage 1+2a+2b meta-analysis identified a second signal at KCNQ1 and a novel HLA-B locus. Secondary analysis including body mass index (BMI) adjustment in stage 1+2a meta-analysis identified the second novel locus at INS-IGF2 (Table 1 and Figure 1). None of the most strongly associated SNPs at these loci demonstrated significant heterogeneity of effect sizes among studies within each stage, between African Americans in stages 1 and 2a, or between African Americans in stage 1+2a and Europeans in stage 2b after Bonferroni correction of multiple comparisons (P_het>0.001) (Figure S1).

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Figure 1. Association results of stage 1 meta-analysis in African Americans in a model adjusted for age, sex, study sites and study-specific principle components.

(A) Manhattan plot. Previously identified loci are denoted in red. Novel loci identified in this study are denoted in blue. (B) Quantile-quantile plot. The observed P values (y axis) were compared with the expected P values under the null distribution (x axis).

https://doi.org/10.1371/journal.pgen.1004517.g001

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Table 1. Novel and previously identified loci associated with T2D at P<5×10⁻⁸.

https://doi.org/10.1371/journal.pgen.1004517.t001

At the TCF7L2 locus, the most strongly associated SNP in stage 1+2a African Americans samples was rs7903146 (OR = 1.33, P = 4.78×10⁻⁴⁴, Table 1 and Figure 2). rs7903146 is also the index SNP (most significantly associated with T2D in prior studies) in Europeans (OR = 1.40, P = 2.21×10⁻⁵¹) [3], South Asians (OR = 1.25, P = 3.4×10⁻¹⁹) [4] and East Asians (OR = 1.48, P = 2.44×10⁻¹⁵) [13].

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Figure 2. Regional plots of five previously and newly identified T2D loci in African Americans.

Association P values (on a −log₁₀ scale) of genotyped and imputed SNPs from stage 1 meta-analysis are plotted as a function of genomic position (NCBI Build 36). Plots for HLA-B, TCF7L2, KCNQ1, and HMGA2 used the model without BMI adjustment whereas plots for INS-IGF2 used the model with BMI adjustment. In each panel, the most strongly associated SNP from stage 1 and stage 1+2a+2b meta-analysis is denoted by a purple circle and a purple diamond, respectively. The color of all other SNPs indicates LD with the most strongly associated SNP based on the HapMap 2 YRI data. At KCNQ1, two independent signals are shown.

https://doi.org/10.1371/journal.pgen.1004517.g002

Two association signals were observed at KCNQ1 (Table 1 and Figure 2). The first association signal was represented by rs2283228 located at the 3′ end of KCNQ1 (stage 1+2a OR = 1.20, P = 9.90×10⁻¹¹; stage 1+2a+2b OR = 1.19, P = 4.87×10⁻¹³). Using data from individuals of African ancestry in Southwest USA (ASW) from the 1000 Genomes Project (1KGP) [14], rs2283228 mapped to the same linkage disequilibrium (LD)-based interval as index SNPs from other populations (rs2283228 [15] and rs2237892 [16]–[17] in Japanese, rs2237892 in Hispanics [18], rs163182 [19] and rs2237895 [20] in Han Chinese). The second association signal was represented by rs231356 (r² = 0 with rs2283228 in both ASW and CEU) (stage 1+2a OR = 1.11, P = 1.94×10⁻⁵; stage 1+2a+2b OR = 1.09, P = 3.93×10⁻⁸), located 144 kb upstream of the first signal. rs231356 is located at the same LD interval as the index SNPs rs231362 in Europeans [3] and rs231359 in Chinese [20].

At the HMGA2 locus, the most strongly associated SNP was rs343092 (stage 1+2a OR = 1.16, P = 8.79×10⁻⁹; stage 1+2a+2b OR = 1.14, P = 2.75×10⁻¹²; Table 1 and Figure 2). rs343092 is located 76 kb downstream and at the same LD interval as of the index SNP rs1531343 reported in Europeans [3].

Two novel T2D loci were identified. The effect sizes of rs2244020 located near HLA-B were similar in African Americans and Europeans (OR = 1.11 vs. 1.07, P_het = 0.26; stage 1+2a+2b P = 6.57×10⁻⁹) (Table 1 and Figure 2). HLA-B encodes the class I major histocompatibility complex involved in antigen presentation in immune responses.

The most strongly associated SNP near INS-IGF2 was rs3842770 in African Americans (OR = 1.14, P = 2.78×10⁻⁸, stage 1+2a BMI adjusted, Table 1 and Figure 2) but the risk A allele was absent in the CEU population. Insulin plays a key role in glucose homeostasis. Mutations at INS lead to neonatal diabetes, type 1 diabetes, and hyperinsulinemia [21]. Insulin-like growth factor 2 (IGF2) is involved in growth and development. IGF2 overexpression in transgenic mice leads to islet hyperplasia [22] and IGF2 deficiency in the Goto–Kakizaki rat leads to beta cell mass anomaly [23].

Discussion

We have performed the largest genetic association analysis to date for T2D in African Americans. Our data support the hypothesis that risk for T2D is partly attributable to a large number of common variants with small effects [7]. We identified HLA-B and INS-IGF2 as novel T2D loci, the latter specific to African Americans. We found evidence supporting association for 88 previously identified T2D and glucose homeostasis loci. Taken together, these 90 loci yielded a sibling relative risk of 1.19. The phenotypic variance measured on the liability scale is substantially larger in African Americans than in European Americans (17.5% vs. 5.7%) [7] due to larger effect sizes upon fine-mapping as well as higher disease prevalence in African Americans.

The two novel T2D loci, HLA-B and INS-IGF2, have been implicated in type 1 diabetes (T1D) risk in Europeans [33]–[35]. One limitation of our study is the lack of autoantibody measurement. However, our results are unlikely to be confounded by the presence of misclassified patients. Among diabetic youth aged <20 years, T2D characterized by insulin resistance without autoimmunity is more prevalent in African Americans (40.1%) than in European Americans (6.2%), while African Americans less often present with autoimmunity and insulin deficiency resembling T1D compared to European Americans (32.5% vs. 62.9%, respectively) [36]. Autoimmunity is also uncommon in African American diabetic adults [37]. Furthermore, associations for T1D are stronger at HLA class II (HLA-DRB1, -DQA1, and -DQB1) than HLA class I regions in Europeans [33]–[34], [38]–[41] (http://www.t1dbase.org). In African Americans, T1D individuals showed both shared and unique risk and protective HLA class II haplotypes as compared to European T1D individuals [42]–[43]. More importantly, these individuals also showed substantially stronger associations at HLA class II (P<1×10⁻²⁵) than class I regions (P<1×10⁻⁵) [42], which is in contradiction with our finding of stronger associations at HLA class I than class II regions in T2D individuals (HLA-B, Figure S4). The observed HLA-B association may be due to LD with nearby causal gene(s) since there is long range LD in this region. Recently, rs3130501 near POU5F1 and TCF19 was reported for association with T2D in a trans-ancestry meta-analysis [8]. rs3130501 was located 211 kb upstream of rs2244020 and mapped to the same LD interval. However, the two SNPs were not correlated in both CEU (D′ = 0.57, r² = 0.05) and ASW (D′ = 0.68, r² = 0.16) from 1KGP nor strongly associated with T2D in the stage 1 meta-analysis (P = 0.04). Other potential non-HLA candidate genes may include TNFA which regulates immune and inflammatory response. It has been hypothesized that activated innate and adaptive immune cells stimulate release of cytokines such as TNFα and IL-1β, which promote both systemic insulin resistance and β-cell damage [44]. On the other hand, evidence has implicated T1D loci HLA-DQ/DR, GLIS3 and INS in the susceptibility of latent autoimmune diabetes in adults (LADA) and/or T2D [7], [34], [45]–[46], while T2D loci such as PPARG and TCF7L2 was associated with T1D [47] and LADA [46], [48], respectively. More comprehensive studies are needed to understand the shared and distinct genetic risks in different forms of diabetes which will facilitate diagnosis and personalized treatment.

Our results have several implications regarding the genetic architecture of T2D. First, fine-mapping suggests that currently known loci explain more of the risk than previously estimated. Second, the loci conferring the largest risk for T2D appear to act through regulatory rather than protein-coding changes. Third, many, but not all, of the previously identified T2D loci are shared across ancestries. The differential LD structure of African-ancestry populations at shared loci provides an opportunity for fine mapping in trans-ethnic meta-analysis. Fourth, the ∼2.6M MEDIA SNPs achieved only 43.3% coverage of the 1KGP ASW common SNPs, suggesting that risk loci that are specific to African-ancestry individuals are difficult to discover with the genotyping arrays being used. Large-scale sequencing studies, such as those focusing on whole genomes, exomes, and targeted resequencing for associated non-coding regions, will be necessary to further delineate the causal variants for T2D risk in African Americans.

Materials and Methods

Supporting Information

Acknowledgments

We thank all the study participants for their valuable contributions to the parent studies (ARIC, CARDIA, CFS, CHS, eMERGE, FamHS, FIND, GeneSTAR, GENOA, HANDLS, Health ABC, HUFS, IPM Biobank, IRAS, IRASFS, JHS, MESA, MESA Family, SCCS, SIGNET-REGARDS, WFSM and WHI) of the MEDIA consortium. We thank the contributions of investigators and staff of the parent studies for data collection, genotyping, data analysis and sharing of association results to the MEDIA consortium at the discovery and replication stages. We also thank the DIAGRAM Consortium for sharing the European T2D GWAS meta-analysis results for replication. We thank the MuTHER Consortium to share the expression quantitative trait loci data. The Candidate-gene Association Resource (CARe) acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the involved research institutions, study investigators, field staff, and study participants of ARIC, CARDIA, CFS, JHS, and MESA in creating the Candidate-gene Association Resource for biomedical research (http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx). The parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology - Broad Institute to create this genotype/phenotype database for wide dissemination to the biomedical research community. Women's Health Initiative (WHI) investigators have reviewed and approved this manuscript. WHI investigators are listed at http://www.whiscience.org/publications/WHI_investigators_shortlist_2010-2015.pdf. The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000200.v1.p1.

Members of the FIND Consortium are:

Genetic Analysis and Data Coordinating Center, Case Western Reserve University, Cleveland, OH: RC Elston, S Iyengar, K Goddard, J Olson, S Ialacci, S Edwards, C Fondran, A Horvath, G Jun, K Kramp, M Slaughter, E Zaletel.

Clinical centers:

Case Western Reserve University, Cleveland, OH: JR Sedor, J Schelling, A Sehgal, A Pickens, L Humbert, L Getz-Fradley.

Harbor—University of California Los Angeles Medical Center: S Adler, HE Collins-Schramm§, E Ipp, H Li§, M. Pahl†, MF Seldin§, J LaPage, B Walker, C Garcia, J Gonzalez, L Ingram-Drake.

§University of California, Davis, CA.

†University of California, Irvine, CA.

Johns Hopkins University, Baltimore, MD: M. Klag, J Coresh, L Kao, L Mead, R Parekh, N Fink, P Bayton, Y Long, L Wei, T Whitehead.

National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ: WC Knowler, RL Hanson, RG Nelson, L Jones, R Juan, R Lovelace, C Luethe, LM Phillips, J Sewemaenewa, I Sili, B Waseta.

University of California, Los Angeles, CA: MF Saad, X Guo, J Rotter, K Taylor, M Budgett.

University of New Mexico, Albuquerque, NM: P Zager, V Shah, M Scavini, A Bobelu.

University of Texas Health Science Center at San Antonio, San Antonio, TX: H Abboud, N Arar, R Duggirala, BS Kasinath, R Plaetke, M Stem, C Goyes, V Sartorio.

Wake-Forest University, Winston-Salem, NC: BI Freedman, DW Bowden, SC Satko, SS Rich, S Warren, S Viverette, G Brooks, R Young.

Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD: C Winkler, MW Smith, M Thompson, R Hanson.

National Institute of Diabetes and Digestive and Kidney Diseases program office: JP Briggs, PL Kimmel, R Rasooly.

External Advisory Committee: D Warnock (chair), R Chakraborty, GM Dunston, RP Lifton, SJ O'Brien (ad hoc), R Spielman.

Members of the eMERGE Consortium are:

Marshfield Clinic, Marshfield, WI: 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.

Northwestern University, Chicago, IL: 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.

Mayo Clinic, Rochester, MN: 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.

Group Health/University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA: 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.

Vanderbilt University, Nashville, TN: 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.

Members of the DIAGRAM Consortium are:

Benjamin F. Voight^1–3,100, Laura J. Scott^4,100, Valgerdur Steinthorsdottir^5,100, Andrew P. Morris^6,100, Christian Dina^7,8,100, Ryan P. Welch⁹, Eleftheria Zeggini^6,10, Cornelia Huth^11,12, Yurii S. Aulchenko¹³, Gudmar Thorleifsson⁵, Laura J. Mcculloch¹⁴, Teresa Ferreira⁶, Harald Grallert^11,12, Najaf Amin¹³, Guanming Wu¹⁵, Cristen J. Willer⁴, Soumya Raychaudhuri^1,2,16, Steve A. Mccarroll^1,17, Claudia Langenberg¹⁸, Oliver M. Hofmann¹⁹, Josée Dupuis^20,21, Lu Qi^22–24, Ayellet V. Segrè^1,2,17, Mandy van Hoek²⁵, Pau Navarro²⁶, Kristin Ardlie¹, Beverley Balkau^27,28, Rafn Benediktsson^29,30, Amanda J. Bennett¹⁴, Roza Blagieva³¹, Eric Boerwinkle³², Lori L. Bonnycastle³³, Kristina Bengtsson Boström³⁴, Bert Bravenboer³⁵, Suzannah Bumpstead¹⁰, Noisël P. Burtt¹, Guillaume Charpentier³⁶, Peter S. Chines³³, Marilyn Cornelis²⁴, David J. Couper³⁷, Gabe Crawford^1, Alex S. F. Doney^38,39, Katherine S. Elliott⁶, Amanda L. Elliott^1,17,40, Michael R. Erdos³³, Caroline S. Fox^21,41, Christopher S. Franklin⁴², Martha Ganser⁴, Christian Gieger¹¹, Niels Grarup⁴³, Todd Green^1,2, Simon Griffin¹⁸, Christopher J. Groves¹⁴, Candace Guiducci¹, Samy Hadjadj⁴⁴, Neelam Hassanali¹⁴, Christian Herder⁴⁵, Bo Isomaa^46,47, Anne U. Jackson⁴, Paul R. V. Johnson⁴⁸, Torben Jørgensen^49,50, Wen H. L. Kao^51,52, Norman Klopp¹¹, Augustine Kong⁵, Peter Kraft^22,23, Johanna Kuusisto⁵³, Torsten Lauritzen⁵⁴, Man Li⁵¹, Aloysius Lieverse⁵⁵, Cecilia M. Lindgren^6, Valeriya Lyssenko⁵⁶, Michel Marre^57,58, Thomas Meitinger^59,60, Kristian Midthjell⁶¹, Mario A. Morken³³, Narisu Narisu³³, Peter Nilsson⁵⁶, Katharine R. Owen¹⁴, Felicity Payne¹⁰, John R. B. Perry^62,63, Ann-Kristin Petersen¹¹, Carl Platou⁶¹, Christine Proença^7, Inga Prokopenko^6,14, Wolfgang Rathmann⁶⁴, N. William Rayner^6,14, Neil R. Robertson^6,14, Ghislain Rocheleau^65–67, Michael Roden^45,68, Michael J. Sampson⁶⁹, Richa Saxena^1,2,40, Beverley M. Shields^62,63, Peter Shrader^3,70, Gunnar Sigurdsson^29,30, Thomas Sparsø⁴³, Klaus Strassburger⁶⁴, Heather M. Stringham⁴, Qi Sun^22,23, Amy J. Swift³³, Barbara Thorand¹¹, Jean Tichet⁷¹, Tiinamaija Tuomi^46,72, Rob M. van Dam²⁴, Timon W. van Haeften⁷³, Thijs van Herpt^25,55, Jana V. van Vliet-Ostaptchouk⁷⁴, G. Bragi Walters⁵, Michael N Weedon^62,63, Cisca Wijmenga⁷⁵, Jacqueline Witteman¹³, the MAGIC investigators⁹⁹, the GIANT consortium⁹⁹, Richard N. Bergman⁷⁶, Stephane Cauchi⁷, Francis S. Collins⁷⁷, Anna L. Gloyn¹⁴, Ulf Gyllensten⁷⁸, Torben Hansen^43,79, Winston A. Hide¹⁹, Graham A. Hitman⁸⁰, Albert Hofman¹³, David J. Hunter^22,23, Kristian Hveem^61,81, Markku laakso⁵³, Karen L. Mohlke⁸², Andrew D. Morris^38,39, Colin N. A. Palmer^38,39, Peter P. Pramstaller⁸³, Igor Rudan^42,84,85, Eric Sijbrands²⁵, Lincoln D. Stein¹⁵, Jaakko Tuomilehto^86–88, Andre Uitterlinden²⁵, Mark Walker⁸⁹, Nicholas J. Wareham¹⁸, Richard M. Watanabe^76,90, Gonçalo R. Abecasis⁴, Bernhard O. Boehm³¹, Harry Campbell⁴², Mark J. Daly^1,2, Andrew T. Hattersley^62,63, Frank B. Hu^22–24, James B. Meigs^3,70, James S. Pankow⁹¹, Oluf Pedersen^43,92,93, H-Erich Wichmann^11,12,94, Inês Barroso¹⁰, Jose C. Florez^1–3,95, Timothy M. Frayling^62,63, Leif Groop^56,72, Rob Sladek^65–67, Unnur Thorsteinsdottir^5,96, James F Wilson⁴², Thomas Illig¹¹, Philippe Froguel^17,97, Cornelia M. van duijn¹³, Kari Stefansson^5,96, David Altshuler 1–3,17,40,95, Michael Boehnke⁴ & Mark I. Mccarthy^6,14,98

1 Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.

2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

3 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

4 Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

5 deCODE Genetics, Reykjavik, Iceland.

6 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

7 CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.

8 INSERM UMR915 CNRS ERL3147, Nantes, France.

9 Bioinformatics Program, University of Michigan, Ann Arbor, Michigan, USA.

10 Wellcome Trust Sanger Institute, Hinxton, UK.

11 Institute of Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany.

12 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

13 Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

14 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

15 Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

16 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

17 Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts, USA.

18 Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

19 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

20 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

21 National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

22 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

23 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

24 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

25 Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands.

26 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

27 INSERM, CESP Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of Diabetes, Obesity and Chronic Kidney Disease over the Lifecourse, Villejuif, France.

28 University Paris-Sud 11, UMRS 1018, Villejuif, France.

29 Landspitali University Hospital, Reykjavik, Iceland.

30 Icelandic Heart Association, Kopavogur, Iceland.

31 Division of Endocrinology, Diabetes and Metabolism, Ulm University, Ulm, Germany.

32 The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA.

33 National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA.

34 Research and Development Centre, Skaraborg Primary Care, Skövde, Sweden.

35 Department of Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands.

36 Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.

37 Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

38 Diabetes Research Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.

39 Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.

40 Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

41 Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

42 Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

43 Hagedorn Research Institute, Gentofte, Denmark.

44 Centre Hospitalier Universitaire de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0801, INSERM U927, Université de Poitiers, UFR, Médecine Pharmacie, Poitiers Cedex, France.

45 Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

46 Folkhälsan Research Center, Helsinki, Finland.

47 Malmska Municipal Health Center and Hospital, Jakobstad, Finland.

48 Diabetes Research and Wellness Foundation Human Islet Isolation Facility and Oxford Islet Transplant Programme, University of Oxford, Oxford, UK.

49 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.

50 Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

51 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

52 Department of Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.

53 Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.

54 Department of General Medical Practice, University of Aarhus, Aarhus, Denmark.

55 Department of Internal Medicine, Maxima Medical Center, Eindhoven, The Netherlands.

56 Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, Malmö, Sweden.

57 Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.

58 INSERM U695, Université Paris 7, Paris, France.

59 Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.

60 Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, München, Germany.

61 Nord-Trøndelag Health Study (HUNT) Research Center, Department of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim, Norway.

62 Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.

63 Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.

64 Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

65 Department of Human Genetics, McGill University, Montreal, Canada.

66 Department of Medicine, Faculty of Medicine, McGill University, Montreal, Canada.

67 McGill University and Genome Quebec Innovation Centre, Montreal, Canada.

68 Department of Metabolic Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

69 Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital National Health Service Trust, Norwich, UK.

70 General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

71 Institut interrégional pour la Santé (IRSA), La Riche, France.

72 Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

73 Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

74 Molecular Genetics, Medical Biology Section, Department of Pathology and Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

75 Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

76 Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California, USA.

77 National Institute of Health, Bethesda, Maryland, USA.

78 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

79 University of Southern Denmark, Odense, Denmark.

80 Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

81 Department of Medicine, The Hospital of Levanger, Levanger, Norway.

82 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

83 Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy.

84 Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split, Croatia.

85 Institute for Clinical Medical Research, University Hospital ‘Sestre Milosrdnice’, Zagreb, Croatia.

86 Department of Public Health, University of Helsinki, Helsinki, Finland.

87 South Ostrobothnia Central Hospital, Seinäjoki, Finland.

88 Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain.

89 Diabetes Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

90 Department of Preventative Medicine, Keck Medical School, University of Southern California, Los Angeles, California, USA.

91 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.

92 Department of Biomedical Science, Panum, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

93 Faculty of Health Science, University of Aarhus, Aarhus, Denmark.

94 Klinikum Grosshadern, Munich, Germany.

95 Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

96 Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

97 Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.

98 Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.

99 A full list of members is provided in the supplementary Note of the original publication.

100 These authors contributed equally

Members of the MuTHER Consortium are:

Kourosh R. Ahmadi¹, Chrysanthi Ainali², Amy Barrett³, Veronique Bataille¹, Jordana T. Bell^1,4, Alfonso Buil⁵, Panos Deloukas⁶, Emmanouil T. Dermitzakis⁵, Antigone S. Dimas^4,5, Richard Durbin⁶, Daniel Glass¹, Elin Grundberg^1,6, Neelam Hassanali³, Åsa K. Hedman⁴, Catherine Ingle⁶, David Knowles⁷, Maria Krestyaninova⁸, Cecilia M. Lindgren⁴, Christopher E. Lowe^9,10, Mark I. McCarthy^3,4,11, Eshwar Meduri ^1,6, Paola di Meglio¹², Josine L. Min⁴, Stephen B. Montgomery⁵, Frank O. Nestle¹², Alexandra C. Nica⁵, James Nisbet⁶, Stephen O'Rahilly^9,10, Leopold Parts⁶, Simon Potter⁶, Magdalena Sekowska⁶, So-Youn Shin⁶, Kerrin S. Small^1,6, Nicole Soranzo^1,6, Tim D. Spector¹, Gabriela Surdulescu¹, Mary E. Travers³, Loukia Tsaprouni⁶, Sophia Tsoka², Alicja Wilk⁶, Tsun-Po Yang⁶, Krina T. Zondervan⁴

1. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK

2. Department of Informatics, School of Natural and Mathematical Sciences, King's College London, Strand, London, UK

3. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, UK

4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

5. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

6. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

7. University of Cambridge, Cambridge, UK

8. European Bioinformatics Institute, Hinxton, UK

9. University of Cambridge Metabolic Research Labs, Institute of Metabolic Science Addenbrooke's Hospital Cambridge, UK

10. Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK

11. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK

12. St. John's Institute of Dermatology, King's College London, London, UK