a genome-wide association study identifies and rasgrp1grk5 ... · chinese hans and recruited...

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©2012 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0454/-/DC1

A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans Description of the Study Samples The samples for the stage 1 genome-wide association testing, comprising 1,999 type 2 diabetic cases (Beijing: 1,000; Shanghai: 999) and 1,976 nondiabetic controls (Beijing: 1,003; Shanghai: 973), were selected from 4 studies (NHAPC, GMOS, FDHS and BDS). The samples for the stage 2 replication, comprising 6,570 type 2 diabetes (T2D) cases and 6,911 controls, were collected by collaborative institutes in Guizhou (the Southwest China), Beijing (the Northern China), and Hubei (the Central China). The stage 3 replication included de novo genotyping in 3,410 T2D cases and 3,412 controls recruited from Shanghai (the Southeast China) and in silico replication in the GWAS datasets (6,952 cases and 11,865 controls) from the studies participating in the Asian Genetic Epidemiology Network consortium of Type 2 Diabetes (AGEN-T2D). The controls were matched to cases in geographical profile. All participants were unrelated Chinese Hans, with the exception of those from AGEN-T2D which included 8,680 Chinese Hans, 2,335 Japanese, 3,985 Korean, 2,034 Malay, and 1,783 Filipino. All studies were approved by local ethnic committees of each participating institution, and written informed consents were obtained from all participants. A summary of the studies included in stage1, 2 and 3 can be found in Table S1, and additional details are provided below.

1. Stage 1 GWA scan Nutrition and Health of Aging Population in China (NHAPC) The Nutrition and Health of Aging Population in China (NHAPC) is a population-based cohort study among 3,289 individuals (3,210 of them are Chinese Hans), aged 50 to 70 years, recruited from Beijing and Shanghai. The study design, methods and measurements of this cohort study have been described in detail elsewhere(1). Briefly, the participants were recruited using a multistage sampling method from 2 urban districts and 1 rural district of each city. Data on demographic variables, health status, health behavior, and physical activity was collected using a standardized questionnaire, and standard anthropometric measurements and overnight fasting blood samples were collected using a standardized protocol when the participants attended a physical examination. Totally, 312 type 2 diabetic cases (Beijing: 202; Shanghai: 110) and 815 nondiabetic controls (Beijing: 344; Shanghai: 471) were selected as the stage 1 samples of this study. The selected type 2 diabetic cases had at least two of the following components: 1) fasting glucose ≥ 7.0 mmol/l; 2) HbA1c ≥ 6.5%; 3) previously diagnosed T2D. The nondiabetic controls met all of the following criteria: 1) no prior history of diabetes; 2) fasting glucose < 5.6 mmol/l; 3) HbA1c < 5.6%; 4) no family history of T2D. Gut Microbiota and Obesity Study (GMOS) The Gut Microbiota and Obesity Study (GMOS), conducted from November 2007 to January 2008, was a population based case-control study comprising 559 overweight/obese and 500 normal-weight participants (35-54 years old) recruited through advertisement in Shanghai. The study population, design and protocols of this population-based case-control study have been previously described in detail(2). A total of 82 type 2 diabetic cases and 163 nondiabetic controls from GMOS were used for the stage 1 genome-wide association testing of this study. T2D cases were defined as those with fasting glucose ≥ 7.0 mmol/l and HbA1c ≥ 6.5%. Control subjects were included if they had fasting plasma glucose < 5.6 mmol/l, HbA1c < 5.6%, no family history of diabetes and no prior history of diabetes. Beijing Diabetes Survey (BDS) The Beijing Diabetes Survey (BDS), conducted from June 2007 to May 2008 in Beijing, was a cross-sectional study, in which 4,860 Beijing residents (1,453 male, 3,407 female), aged 20 to 86 years, were recruited in the Mentougou district, the Haidian district, the Tongzhou district, the Fengtai district and the Pinggu district. Information on demographic characteristics, personal and family medical history,

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lifestyle risk factors, and anthropometric measurements were collected either by questionnaire or by standard protocols in local hospitals or community health centers. All participants underwent a 75g oral glucose tolerance test (OGTT) after an overnight fast of more than 10 hours, and venous blood specimen were collected for testing plasma glucose and insulin concentrations at 0 and 2 hours during the test. For the participants with no history of diabetes, a standard 75g glucose solution was given during the test, while participants with a self-reported history of diabetes were given a steamed bun that contained approximately 80g of complex carbohydrates. In total, 798 type 2 diabetic cases (362 male, 436 female) and 659 controls (320 male, 355 female), aged 35-80, from the Beijing participants were used for the stage 1 genome-wide association scan of this study. T2D was defined by the 1999 WHO criteria (fasting glucose ≥ 7.0 mmol/l and 2-hour plasma glucose ≥ 11.1 mmol/l during an OGTT). The nondiabetic controls were those met all the following criteria: 1) no prior history of T2D; 2) no family history of T2D; 3) fasting glucose < 5.6 mmol/l; 4) 2-hour plasma glucose < 7.8 mmol/l in a 75g OGTT. Fudan-Huashan Study (FDHS) The Fudan-Huashan Study (FDHS) is a case-control study comprising 807 type 2 diabetic cases ( 351 male and 456 female) and 339 nondiabetic controls (136 male and 203 female), aged 30 to 85 years, recruited from Simenerlu Community of the Jingan District and Jiangninglu Community of the Putuo District in Shanghai. All participants completed a standardized questionnaire to collect information on demographic data, life style and health status. Anthropometric measurements and fasting blood samples were collected when the participants attended a physical examination. All participants received 2-hour 75g OGTT except for previously diagnosed T2D patients. T2D was defined by 1999 WHO criteria or previously diagnosed T2D. All the T2D cases were negative for glutamic acid decarboxylase (GAD) and insulin autoantibody (IAA) tests. Controls were selected based on the following criteria: 1) no prior history of diabetes; 2) no family history of diabetes; 3) fasting plasma glucose < 5.6 mmol/l; and 4) 2-hour glucose < 7.8 mmol/l in a standard 75g OGTT. All participants were included into the stage 1 genome-wide association scan of this study.

2. Stage 2 replication study (96 SNPs) Guizhou-Bijie Type 2 Diabetes Study (GBTDS) The Gouzhou-Bijie Type 2 Diabetes Study (GBTDS) is a population-based case-control study conducted from September 2009 to January 2010 in Bijie city of Guizhou province. The participants include 1,824 type 2 diabetic cases (955 male and 869 female) and 1,719 nondiabetic controls (828 male and 891 female) aged 30 to 80 years, with at least 10 years residence in Bijie city. All participants are unrelated Chinese Hans and recruited through advertisement. The participants were asked to attend a complete physical examination in the Bijie People’s Hospital to collect standard anthropometric measurements and blood samples, and to complete a comprehensive questionnaire to collect information on demographic variables, health status, health behavior, and physical activity. All participants were given a standard 2 hour 75-g OGTT unless they were previously diagnosed as having T2D and currently receiving antidiabetic treatment. The T2D cases were identified as previously diagnosed T2D and currently on medication, or met all the following criteria: 1) fasting glucose ≥ 7.0 mmol/L; 2) 2-hour plasma glucose ≥ 11.1 mmol/l or HbA1c ≥ 6.5%. The inclusion criteria for the controls, who were residents in the same communities as the cases, were as follows: 1) no prior history of diabetes; 2) no family history of T2D; 3) fasting glucose < 6.1 mmol/l and 2-hour plasma glucose < 7.8 mmol/l. Beijing Type 2 Diabetes Studies (BTDS), incorporating three case-control studies The study population included 3,114 type 2 diabetic cases (1,461 men, 1,653 women) and 3,513 nondiabetic controls (1,759 men, 1,754 women) from three hospital-based case-control studies, originally led by the Peking University People’s Hospital (1,235 cases and 1,376 controls), the Beijing Hospital (1,337 cases and 1,573 controls) and the Peking Union Medical College (542 cases and 564 controls). The T2D cases were consecutively recruited by the collaborating clinicians at the out-patient or in-patient departments of the Peking University People’s Hospital, the Beijing Hospital and the

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Peking Union Medical College Hospital. The nondiabetic controls, matched largely to the age and geographic distribution of the cases, were recruited either at the physical examination centers of the three hospitals or from population-based diabetes-screening program in Beijing during the same period using same study protocol. All participants completed a comprehensive epidemiological questionnaire to collect information on health status, and family history of diabetes, and attended a physical examination to collect anthropometric measurements and blood samples. Type 2 diabetic cases were identified by 1999 WHO criteria or as those who met the following criteria: 1) fasting plasma glucose ≥ 7.0 mmol/l, 2) 2-hour plasma glucose ≥ 11.1 mmol/l in OGTT or plasma HbA1c ≥ 6.5%. All the T2D cases from the Peking University People’s Hospital were negative for glutamic acid decarboxylase (GAD) and insulin autoantibody (IAA) tests. The nondiabetic controls were selected based on the following criteria: 1) no prior personal history of diabetes and no family history of diabetes, 2) fasting glucose < 6.1 mmol/l, 3) 2-hour plasma glucose < 7.8 mmol/l in OGTT and/or HbA1c content < 6.5%. Hubei Type 2 Diabetes Studies (HTDS), incorporating DFTJ and TMCS The Dongfeng Tongji study (DFTJ) is an ongoing population-based cohort study, starting from 2008, with 27,009 participants (age 45-90 years) recruited from the Dongfeng Motor Corporation in the Hubei province. All participants completed a semi-structured questionnaire to provide epidemiological information, and attended a health examination in which standard anthropometric measurements and fasting blood samples were collected. From them, 655 type 2 diabetic patients (251 male and 404 female) and 1,331 nondiabetic controls (544 male and 787 female), residing in the same communities as the cases, were used for the stage 2 replication of this study. The type 2 diabetic cases were identified as those who self-reported to have T2D and were verified through review of medical/hospital records according to 1999 WHO criteria. The control subjects met all the following criteria: 1) with no personal history of diabetes; 2) no family history of diabetes; 3) fating glucose < 6.1 mmol/l; 4) BMI ≤ 35 kg/m2. The Tongji Medical College Study (TMCS) is a hospital-based case-control study comprising 977 type 2 diabetic cases (570 men, 407 women) and 384 nondiabetic controls (242 men, 142 women). All the participants, aged 35 to 85, were recruited by collaborating clinicians at the physical examination center or outpatient clinic of Endocrinology Department of the Tongji Hospital in Hubei province. Type 2 diabetic cases were identified as those with previously diagnosed T2D and current use of antidiabetic treatment or who has fasting plasma glucose ≥ 7.0 mmol/l and 2-hour plasma glucose ≥ 11.1 mmol/l in OGTT. The nondiabetic controls were selected according to the following criteria: 1) no past history of diagnosis of diabetes; 2) no family history of diabetes; 3) fasting glucose < 6.1 mmol/l.

3. Stage 3 replication study (10 SNPs) The stage 3 replication consisted of a de novo genotyping in 3,410 T2D cases and 3,412 controls, and an in silico replication with GWAS datasets of 6,952 cases and 11,865 controls from the AGEN-T2D consortium. The cases for the de novo genotyping were drawn from the Shanghai Diabetes Inpatient Database (SDIID), and the controls from the Shanghai Diabetes Study (SDS), which are both led by Shanghai Jiao Tong University. De novo genotyping, incorporating SDIID and SDS The Shanghai Diabetes Inpatient Database (SDIID) comprises over 6,000 of both type 1 and T2D, and some diabetes-related genetic syndromes (e.g., Parder Willi, Rabson Manderhall), which were consecutively recruited from 2001 up to now at the Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. All participants underwent a detailed clinical investigation and detailed phenotypes of glucose and lipid metabolism, blood pressure, liver and kidney function, and diabetic complications were collected (3-5). The Shanghai Diabetes Study (SDS) was a cross-sectional survey(3) conducted in two urban communities in Shanghai. The stage I survey (SDS I) was conducted in 1998–2001 with 5,994 participants being recruited, and the stage II survey (SDS II) was conducted in 2007-2008, with additional 5,372 participants being recruited. The type 2 diabetic cases were identified by the 1999 WHO criteria (fasting plasma glucose ≥ 7.0 mmol/l and/or 2-

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hour plasma glucose ≥ 11.1 mmol/l) and were on medication with oral hypoglycaemic agents and/or insulin. All the T2D cases were negative for glutamic acid decarboxylase (GAD) and insulin autoantibody (IAA) tests. The controls had normal glucose tolerance, defined as a fasting plasma glucose level < 6.1 mmol/l and a 2-hour plasma glucose level < 7.8 mmol/l in 75 g OGTT. All the controls had no family history of diabetes according to self-report questionnaire data. All the case and control subjects were Shanghai residents of Chinese Han ancestry. In silico replication in AGEN-T2D datasets In silico replication for T2D associations of the 10 candidate SNPs were performed in 6,952 cases and 11,865 controls from eight GWAS studies (KARE, SDCS, SP2, SiMES, CAGE, SDGS, TDS and CLHNS) participating in the AGEN-T2D consortium (6) (Table S1). The study samples consisted of 8,680 Chinese Hans (4,026 cases and 4,654 controls), 2,335 Japanese (931 cases and 1,404 controls), 3,985 Korean (1,042 cases and 2,943 controls), 2,034 Malay (794 cases and 1,240 controls), and 1,783 Filipino (159 cases and 1,624 controls). The criteria for T2D case and control have been described previously in detail 6l . Reference 1. Wu Y, Li H, Loos RJF, Yu Z, Ye X, Chen L, Pan A, Hu FB, Lin X: Common variants in CDKAL1,

CDKN2A/B, IGF2BP2, SLC30A8 and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 2008;57:2834–2842

2. Sun L, Yu Z, Ye X, Zou S, Li H, Yu D, Wu H, Chen Y, Dore J, Cl茅ment K, Hu FB, Lin X: A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care 2010;33:1925–1932

3. Jia WP, Pang C, Chen L, Bao YQ, Lu JX, Lu HJ, Tang JL, Wu YM, Zuo YH, Jiang SY, Xiang KS: Epidemiological characteristics of diabetes mellitus and impaired glucose regulation in a Chinese adult population: the Shanghai Diabetes Studies, a cross-sectional 3-year follow-up study in Shanghai urban communities. Diabetologia 2007;50:286-292

4. Hu C, Wang C, Zhang R, Ng MC, Bao Y, So WY, Ma RC, Ma X, Chan JC, Xiang K, Jia W: Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population. Diabetologia 2010;53:290-298

5. Bao Y, Ma X, Li H, Zhou M, Hu C, Wu H, Tang J, Hou X, Xiang K, Jia W: Glycated haemoglobin A1c for diagnosing diabetes in Chinese population: cross sectional epidemiological survey. BMJ 2010;340:c2249

6. Cho YS, Chen CH, Hu C, Long J, Hee Ong RT, Sim X, Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang YC, Kwak SH, Ma RC, Yamamoto K, Adair LS, Aung T, Cai Q, Chang LC, Chen YT, Gao Y, Hu FB, Kim HL, Kim S, Kim YJ, Lee JJ, Lee NR, Li Y, Liu JJ, Lu W, Nakamura J, Nakashima E, Ng DP, Tay WT, Tsai FJ, Wong TY, Yokota M, Zheng W, Zhang R, Wang C, So WY, Ohnaka K, Ikegami H, Hara K, Cho YM, Cho NH, Chang TJ, Bao Y, Hedman AK, Morris AP, McCarthy MI, Takayanagi R, Park KS, Jia W, Chuang LM, Chan JC, Maeda S, Kadowaki T, Lee JY, Wu JY, Teo YY, Tai ES, Shu XO, Mohlke KL, Kato N, Han BG, Seielstad M: Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 2011;44:67-72

Members of the DIAGRAM Consortium Benjamin F Voight1,2,3, Laura J Scott4, Valgerdur Steinthorsdottir5, Andrew P Morris6, Christian Dina7,8, Ryan P Welch9, Eleftheria Zeggini6,10, Cornelia Huth11,12, Yurii S Aulchenko13, Gudmar Thorleifsson5, Laura J McCulloch14, Teresa Ferreira6, Harald Grallert11,12, Najaf Amin13, Guanming Wu15, Cristen J Willer4, Soumya Raychaudhuri1,2,16, Steve A McCarroll1,17, Claudia Langenberg18, Oliver M Hofmann19,

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Josée Dupuis20,21, Lu Qi22-24, Ayellet V Segrè1,2,17, Mandy van Hoek25, Pau Navarro26, Kristin Ardlie1, Beverley Balkau27,28, Rafn Benediktsson29,30, Amanda J Bennett14, Roza Blagieva31, Eric Boerwinkle32, Lori L Bonnycastle33, Kristina Bengtsson Boström34, Bert Bravenboer35, Suzannah Bumpstead10, Noël P Burtt1, Guillaume Charpentier36, Peter S Chines33, Marilyn Cornelis24, David J Couper37, Gabe Crawford1, Alex SF Doney38,39, Katherine S Elliott6, Amanda L Elliott1,17,40, Michael R Erdos33, Caroline S Fox21,41, Christopher S Franklin42, Martha Ganser4, Christian Gieger11, Niels Grarup43, Todd Green1,2, Simon Griffin18, Christopher J Groves14, Candace Guiducci1, Samy Hadjadj44, Neelam Hassanali14, Christian Herder45, Bo Isomaa46,47, Anne U Jackson4, Paul RV Johnson48, Torben Jørgensen49,50, Wen HL Kao51,52, Norman Klopp11, Augustine Kong5, Peter Kraft22,23, Johanna Kuusisto53, Torsten Lauritzen54, Man Li51, Aloysius Lieverse55, Cecilia M Lindgren6, Valeriya Lyssenko56, Michel Marre57,58, Thomas Meitinger59,60, Kristian Midthjell61, Mario A Morken33, Narisu Narisu33, Peter Nilsson56, Katharine R Owen14, Felicity Payne10, John RB Perry62,63, Ann-Kristin Petersen11, Carl Platou61, Christine Proença7, Inga Prokopenko6,14, Wolfgang Rathmann64, N William Rayner6,14, Neil R Robertson6,14, Ghislain Rocheleau65-67, Michael Roden45,68, Michael J Sampson69, Richa Saxena1,2,40, Beverley M Shields62,63, Peter Shrader3,70, Gunnar Sigurdsson29,30, Thomas Sparsø43, Klaus Strassburger64, Heather M Stringham4, Qi Sun22,23, Amy J Swift33, Barbara Thorand11, Jean Tichet71, Tiinamaija Tuomi46,72, Rob M van Dam24, Timon W van Haeften73, Thijs van Herpt25,55, Jana V van Vliet-Ostaptchouk74, G Bragi Walters5, Michael N Weedon62,63, Cisca Wijmenga75, Jacqueline Witteman13, Richard N Bergman76, Stephane Cauchi7, Francis S Collins77, Anna L Gloyn14, Ulf Gyllensten78, Torben Hansen43,79, Winston A Hide19, Graham A Hitman80, Albert Hofman13, David J Hunter22,23, Kristian Hveem61,81, Markku Laakso53, Karen L Mohlke82, Andrew D Morris38,39, Colin NA Palmer38,39, Peter P Pramstaller83, Igor Rudan42,84,85, Eric Sijbrands25, Lincoln D Stein15, Jaakko Tuomilehto86, Andre Uitterlinden25, Mark Walker87, Nicholas J Wareham18, Richard M Watanabe76,88, Goncalo R Abecasis4, Bernhard O Boehm31, Harry Campbell42, Mark J Daly1,2, Andrew T Hattersley62,63, Frank B Hu22-24, James B Meigs3,70, James S Pankow89, Oluf Pedersen43,90,91, H.-Erich Wichmann11,12,92, Inês Barroso10, Jose C Florez1,2,3,93, Timothy M Frayling62,63, Leif Groop56,72, Rob Sladek65-67, Unnur Thorsteinsdottir5,94, James F Wilson42, Thomas Illig11, Philippe Froguel7,95, Cornelia M van Duijn13, Kari Stefansson5,94, David Altshuler1,2,3,17,40,93, Michael Boehnke4, Mark I McCarthy6,14,96.

Affiliations

1. Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02142, USA

2. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

3. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA 4. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109-2029, USA 5. deCODE Genetics, 101 Reykjavik, Iceland 6. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK 7. CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, F-59019 Lille, France 8. INSERM UMR915 CNRS ERL3147 F-44007 Nantes, France 9. Bioinformatics Program, University of Michigan, Ann Arbor MI USA 48109 10. Wellcome Trust Sanger Institute, Hinxton, CB10 1HH, UK 11. Institute of Epidemiology, Helmholtz Zentrum Muenchen, 85764 Neuherberg, Germany 12. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, 81377

Munich, Germany

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13. Department of Epidemiology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

14. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX3 7LJ, UK 15. Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3,

Canada 16. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical

School, Boston, Massachusetts 02115, USA 17. Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts 02115, USA 18. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2

0QQ, UK 19. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA 20. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118,

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

01702, USA 22. Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115,

USA 23. Department of Epidemiology, Harvard School of Public Health, 665 Huntington Ave, Boston, MA

02115, USA 24. Channing Laboratory, Dept. of Medicine, Brigham and Women's Hospital and Harvard Medical School,

181 Longwood Ave, Boston, MA 02115, USA 25. Department of Internal Medicine, Erasmus University Medical Centre, PO-Box 2040, 3000 CA

Rotterdam, The Netherlands 26. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital,

Edinburgh, EH4 2XU, UK 27. INSERM U780, F-94807 Villejuif. France 28. University Paris-Sud, F-91405 Orsay, France 29. Landspitali University Hospital, 101 Reykjavik, Iceland 30. Icelandic Heart Association, 201 Kopavogur, Iceland 31. Division of Endocrinology, Diabetes and Metabolism, Ulm University, 89081 Ulm, Germany 32. The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science

Center, Houston, Texas 77030, USA 33. National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland 20892,

USA 34. R&D Centre, Skaraborg Primary Care, 541 30 Skövde, Sweden 35. Department of Internal Medicine, Catharina Hospital, PO-Box 1350, 5602 ZA Eindhoven, The

Netherlands 36. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, F-91100 Corbeil-Essonnes, France 37. Department of Biostatistics and Collaborative Studies Coordinating Center, University of North

Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA 38. Diabetes Research Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital,

Dundee DD1 9SY, UK 39. Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital,

Dundee DD1 9SY, UK 40. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA 41. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard

Medical School, Boston, Massachusetts 02115, USA

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42. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK

43. Hagedorn Research Institute, DK-2820 Gentofte, Denmark 44. Centre Hospitalier Universitaire de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0801,

INSERM U927, Université de Poitiers, UFR, Médecine Pharmacie, 86021 Poitiers Cedex, France 45. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at

Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany 46. Folkhälsan Research Center, FIN-00014 Helsinki, Finland 47. Malmska Municipal Health Center and Hospital, 68601 Jakobstad, Finland 48. Diabetes Research and Wellness Foundation Human Islet Isolation Facility and Oxford Islet Transplant

Programme, University of Oxford, Old Road, Headington, Oxford, OX3 7LJ, UK 49. Research Centre for Prevention and Health, Glostrup University Hospital, DK-2600 Glostrup, Denmark 50. Faculty of Health Science, University of Copenhagen, 2200 Copenhagen, Denmark 51. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21287, USA 52. Department of Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns

Hopkins University, Baltimore, Maryland 21287, USA 53. Department of Medicine, University of Kuopio and Kuopio University Hospital, FIN-70211 Kuopio,

Finland 54. Department of General Medical Practice, University of Aarhus, DK-8000 Aarhus, Denmark 55. Department of Internal Medicine, Maxima MC, PO-Box 90052, 5600 PD Eindhoven, The Netherlands 56. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital

Malmö, Lund University, 205 02 Malmö, Sweden 57. Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital,

Assistance Publique des Hôpitaux de Paris, 75870 Paris Cedex 18, France 58. INSERM U695, Université Paris 7, 75018 Paris , France 59. Institute of Human Genetics, Helmholtz Zentrum Muenchen, 85764 Neuherberg, Germany 60. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675

Muenchen, Germany 61. Nord-Trøndelag Health Study (HUNT) Research Center, Department of Community Medicine and

General Practice, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway 62. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School,

University of Exeter, Magdalen Road, Exeter EX1 2LU, UK 63. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University

of Exeter, Barrack Road, Exeter EX2 5DW, UK 64. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes

Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany 65. Department of Human Genetics, McGill University, Montreal H3H 1P3, Canada 66. Department of Medicine, Faculty of Medicine, McGill University, Montreal, H3A 1A4, Canada 67. McGill University and Genome Quebec Innovation Centre, Montreal, H3A 1A4. Canada 68. Department of Metabolic Diseases, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany 69. Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital NHS Trust ,

Norwich, NR1 7UY, UK.

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70. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA 71. Institut interrégional pour la Santé (IRSA), F-37521 La Riche, France 72. Department of Medicine, Helsinki University Hospital, University of Helsinki, FIN-00290 Helsinki,

Finland 73. Department of Internal Medicine, University Medical Center Utrecht, 3584 CG Utrecht,The Netherlands 74. Molecular Genetics, Medical Biology Section, Department of Pathology and Medical Biology,

University Medical Center Groningen and University of Groningen, 9700 RB Groningen, The Netherlands 75. Department of Genetics, University Medical Center Groningen and University of Groningen, 9713 EX

Groningen, The Netherlands 76. Department of Physiology and Biophysics, University of Southern California School of Medicine, Los

Angeles, California 90033, USA 77. National Institute of Health, Bethesda, Maryland 20892, USA 78. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala,

Sweden. 79. University of Southern Denmark, DK-5230 Odense, Denmark 80. Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University

of London, London E1 2AT, UK 81. Department of Medicine, The Hospital of Levanger, N-7600 Levanger, Norway 82. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA 83. Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso 1, 39100

Bolzano, Italy 84. Croatian Centre for Global Health, Faculty of Medicine, University of Split, Soltanska 2, 21000 Split,

Croatia 85. Institute for Clinical Medical Research, University Hospital "Sestre Milosrdnice", Vinogradska 29,

10000 Zagreb, Croatia 86. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki FIN-

00300, Finland, 87. Diabetes Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place,

Newcastle upon Tyne NE2 4HH, UK 88. Department of Preventitive Medicine, Keck Medical School, University of Southern California, Los

Angeles, CA, 90089-9001, USA 89. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota

55454, USA 90. Department of Biomedical Science, Panum, Faculty of Health Science, University of Copenhagen, 2200

Copenhagen, Denmark 91. Faculty of Health Science, University of Aarhus, DK–8000 Aarhus, Denmark 92. Klinikum Grosshadern, 81377 Munich, Germany 93. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02144, USA 94. Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland 95. Genomic Medicine, Imperial College London, Hammersmith Hospital, W12 0NN, London, UK 96. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old

Road Headington, Oxford, OX3 7LJ, UK Members of the AGEN-T2D Consortium Yoon Shin Cho1,2, Chien-Hsiun Chen3,4, Cheng Hu5, Jirong Long6, Rick Twee Hee Ong7, Xueling Sim8, Fumihiko Takeuchi9, Ying Wu10, Min Jin Go1, Toshimasa Yamauchi11, Yi-Cheng Chang12, Soo Heon Kwak13, Ronald C W Ma14, Ken Yamamoto15, Linda S Adair16, Tin Aung17,18, Qiuyin Cai6, Li-Ching Chang3, Yuan-Tsong Chen3, Yutang Gao19, Frank B Hu20, Hyung-Lae Kim1,21, Sangsoo Kim22, Young

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Jin Kim1, Jeannette Jen-Mai Lee23, Nanette R Lee24, Yun Li10,25, Jian Jun Liu26, Wei Lu27, Jiro Nakamura28, Eitaro Nakashima28,29, Daniel Peng-Keat Ng23, Wan Ting Tay17, Fuu-Jen Tsai4, Tien Yin Wong17,18,30, Mitsuhiro Yokota31, Wei Zheng6, Rong Zhang5, Congrong Wang5, Wing Yee So14, Keizo Ohnaka32, Hiroshi Ikegami33, Kazuo Hara11, Young Min Cho13, Nam H Cho34, Tien-Jyun Chang12, Yuqian Bao5, Ryoichi Takayanagi32, Kyong Soo Park13,35, Weiping Jia5, Lee-Ming Chuang12,36, Juliana C N Chan14, Shiro Maeda37, Takashi Kadowaki11, Jong-Young Lee1, Jer-Yuarn Wu3,4, Yik Ying Teo7,8,23,26,38, E Shyong Tai23,39,40, Xiao Ou Shu6, Karen L Mohlke10, Norihiro Kato9, Bok-Ghee Han1 & Mark Seielstad26,41,42

Affiliations 1. Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Cheongwon-gun, Gangoe-myeon, Yeonje-ri, Republic of Korea. 2. Department of Biomedical Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 200-702, Republic of Korea 3. Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan. 4. School of Chinese Medicine, China Medical University, Taichung, Taiwan 5. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China 6. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 7. Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore 8. Centre for Molecular Epidemiology, National University of Singapore, Singapore, Singapore 9. Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan 10. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA 11. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 12. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 13. Department of Internal Medicine, Seoul National University College of Medicine, Jongno-Gu, Seoul, Republic of Korea 14. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China 15. Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan 16. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA 17. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 18. Department of Ophthalmology, National University of Singapore, Singapore, Singapore 19. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China 20. Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA 21. Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea 22. School of Systems Biomedical Science, Soongsil University, Dongjak-gu, Seoul, Republic of Korea 23. Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore 24. Office of Population Studies Foundation Inc., University of San Carlos, Cebu City, Philippines 25.Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA 26. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore 27. Shanghai Institute of Preventive Medicine, Shanghai, China 28. Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan 29. Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan 30. Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia 31. Department of Genome Science, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan

SUPPLEMENTARY DATA


32. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan 33. Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka-sayama, Osaka, Japan 34. Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Republic of Korea 35. World Class University Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Jongno-Gu, Seoul, Republic of Korea 36. Graduate Institute of Clinical Medicine, National Taiwan University School of Medicine, Taipei, Taiwan 37. Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Japan 38. Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore 39. Department of Medicine, National University of Singapore, Singapore, Singapore 40. Duke-National University of Singapore Graduate Medical School, Singapore, Singapore 41. Institute for Human Genetics, University of California, San Francisco, California, USA 42. Blood Systems Research Institute, San Francisco, California, USA

SUPPLEMENTARY DATA

©2012 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0454/-/DC1

Supplementary Table 1. Study populations

Study Abbreviation Study design Ethnic group Genotyping platform

Group N (male %) Age (years) BMI (kg/m2)

Stage 1 Samples

The Nutrition and Health of Aging Population in China study

NHAPC Cohort, Population-based Chinese Hans, Shanghai

Illumina 660W

Case 110 (56.4) 59.97 (5.58) 25.08 (3.38)

Control 471 (46.5) 58.00 (6.02) 22.87 (3.15)

The Gut Microbiota and Obesity Study GMOS Case-control, population-based

Chinese Hans, Shanghai

Illumina 660W

Case 82 (51.2) 52.13 (8.27) 26.37 (3.81)

Control 163 (41.7) 44.49 (5.49) 22.66 (2.89)

Fudan-Huashan study FDHS Case-control, population-based


Illumina 660W

Case 807 (43.5) 61.05 (8.90) 25.05 (3.55)

Control 339 (40.1) 58.86 (7.74) 24.16 (3.11)

All samples from Shanghai Case 999 (45.5) 60.20 (8.88) 25.16 (3.57)

Control 973 (43.5) 56.04 (8.39) 23.29 (3.15)

The Nutrition and Health of Aging Population in China study

NHAPC Cohort, Population-based Chinese Hans, Beijing

Illumina 660W

Case 202 (46.0) 59.54 (5.75) 25.48 (3.65)

Control 344 (45.3) 57.71 (5.85) 24.49 (3.60)

The Beijing Diabetes Survey BDS Cross-sectional, population-based

Chinese Hans, Beijing

Illumina 660W

Case 798 (45.4) 56.63 (7.80) 24.60 (2.55)

Control 659 (45.1) 49.08 (9.44) 24.71 (2.64)

All Samples from Beijing Case 1,000 (45.5) 57.22 (7.52) 24.78 (2.83)

Control 1,003 (45.2) 52.04 (9.33) 24.63 (3.01)

Stage 2 Samples

Guizhou-Bijie Type 2 Diabetes Study GBTDS Case-control, population-based

Chinese Hans, Guizhou

Fluidigm EPI Case 1,824 (52.4)

56.49 (10.00)

25.25 (3.79)

control 1,719 (48.2) 49.31 (9.53) 24.11 (3.44)

Peking University People's Hospital PUPH Case-control Chinese Hans, Beijing

Fluidigm EPI Case 1,235 (46.0) 56.64 (9.06) 25.46 (3.00)

Control 1,376 (44.1) 51.48 (8.96) 25.12 (3.00)

Beijing Hospital BJH Case-control Chinese Hans, Beijing

Fluidigm EPI Case 1,337 (45.2) 59.42 (7.97) 25.34 (3.30)

Control 1,573 (58.4) 49.49 (12.35)

23.88 (3.06)

Peking Union Medical College PUMC Case-control Chinese Hans, Beijing

Fluidigm EPI Case 542 (53.3) 53.61 (8.82) 25.75 (3.63)

control 564 (41.5) 49.16 (9.59) 24.52 (3.29)

Dongfeng-Tongji study DFTJ Cohort, Population-based Chinese Hans, Fluidigm EPI Case 655 (38.3) 66.23 (7.01) 25.30 (3.12)

SUPPLEMENTARY DATA


Hubei control 1,331 (40.9) 65.92 (7.60) 23.75 (3.44)

Tongji Medical College Study TMCS Case-control Chinese Hans, Hubei

Fluidigm EPI Case 977 (58.3) 51.10 (9.86) 24.80 (3.44)

control 384 (63.0) 47.02 (10.72)

22.78 (3.00)

Stage 3 samples

De novo genotyping

Shanghai Jiao Tong University SDIID/SDS SDIID: case-control, SDS: community-based


Mass ARRAY Case 3,410 (54.8)

60.33 (12.49)

24.38 (3.51)

Control 3,412 (40.0) 50.10 (14.27)

23.46 (3.25)

In silico replication

Korea Association Resource Study KARE Population-based, prospective

Korean Affy 5.0 Case 1,042 NA NA

Control 2,943 NA NA

Singapore Diabetes Cohort Study / Singapore Prospective Study Program

SDCS/SP2 (1) Case-control, multicenter Chinese, Singapore

Illumina 610 Case 1,082 NA NA

Control 1,006 NA NA

SDCS/SP2 (2) Case-control, multicenter Chinese, Singapore

Illumina 1M Case 928 NA NA

Control 939 NA NA

Singapore Malay Eye Study SiMES Population-based, prospective

Malay Illumina 610 Case 794 NA NA

Control 1,240 NA NA

the Japan Cardiometabolic Genome Epidemiology Network

CAGE Case-control, multicenter Japanese Illumina 550 and 610

Case 931 NA NA

Control 1,404 NA NA

Shanghai Diabetes Genetic Study SDGS Population-based Chinese Hans, Shanghai

Affy 6.0 Case 1,019 NA NA

Control 1,710 NA NA

Taiwan T2D study TDS Case-control Chinese, Taiwan Illumina 550 Case 997 NA NA

Control 999 NA NA

Cebu Longitudinal Health and Nutrition Survey

CLHNS Population-based Filipino Affy 5.0 Case 159 NA NA

Control 1,624 NA NA

All samples from AGEN-T2D Case 6,952

> 40 NA Control 11,865

SUPPLEMENTARY DATA


Supplementary Table 2. The 96 SNPs selected for replication in stage 2

SNP Nearest Gene Alleles (R/A)

Pooled analyses Secondary analyses meta-analysis by region by sex subgroup

OR [95%CI] P* PBMI*‡ OR [95%CI]† Pmeta

† PShanghai PBeijing Phetero Pmale Pfemale Pfamilyhist

rs10915140 MATN1 C/T 1.22 [1.10-1.36] 1.62E-04 (2.06E-04)

1.65E-04 (2.13E-04)

1.22 [1.10-1.35] 2.82E-04 3.43E-02 2.12E-03 5.31E-01 2.21E-02 2.80E-03 2.08E-03

rs4949302 LAPTM5 A/G 1.23 [1.11-1.37] 8.25E-05 (1.07E-04)

3.51E-05 (4.75E-05)

1.22 [1.10-1.35] 2.23E-04 4.32E-04 7.17E-02 2.27E-01 2.74E-02 2.70E-03 4.63E-03

rs1134767 INADL G/A 1.22 [1.11-1.34] 4.13E-05 (5.46E-05)

2.98E-05 (4.06E-05)

1.22 [1.11-1.34] 4.35E-05 6.31E-02 7.59E-05 1.31E-01 8.55E-03 2.25E-03 1.85E-05

rs1984285 KCNN3 T/G 1.19 [1.07-1.31] 8.03E-04 (9.71E-04)

1.48E-03 (1.78E-03)

1.19 [1.08-1.31] 7.87E-04 1.47E-02 1.78E-02 9.59E-01 1.39E-01 8.96E-04 2.09E-02

rs4656256 NCSTN G/A 1.21 [1.09-1.33] 1.86E-04 (2.35E-04)

5.99E-05 (7.98E-05)

1.21 [1.09-1.33] 1.91E-04 6.23E-02 5.51E-04 2.51E-01 1.59E-02 4.10E-03 4.48E-06

rs4656902 NHLH1 G/T 1.32 [1.14-1.52] 1.44E-04 (1.83E-04)

6.15E-05 (8.18E-05)

1.31 [1.13-1.51] 2.60E-04 4.66E-01 9.28E-06 9.47E-03 8.04E-03 1.06E-02 3.26E-04

rs12563833 TNN A/G 1.21 [1.10-1.33] 8.25E-05 (1.07E-04)

5.41E-05 (7.23E-05)

1.21 [1.10-1.33] 7.71E-05 2.32E-02 7.46E-04 4.36E-01 1.24E-02 1.89E-03 4.81E-04

rs924569 KCNH1 T/C 1.28 [1.14-1.43] 2.05E-05 (2.77E-05)

2.90E-05 (3.95E-05)

1.28 [1.14-1.43] 3.03E-05 1.87E-05 8.16E-02 7.29E-02 3.09E-03 3.59E-03 2.82E-05

rs1832544 SPATA17 A/G 1.28 [1.13-1.44] 5.33E-05 (6.99E-05)

3.08E-05 (4.19E-05)

1.27 [1.12-1.42] 1.15E-04 1.59E-02 1.94E-03 6.37E-01 4.02E-03 4.11E-03 1.03E-03

rs12028581 IRF2BP2 C/T 1.28 [1.12-1.46] 2.93E-04 (3.65E-04)

3.05E-04 (3.85E-04)

1.27 [1.11-1.45] 4.14E-04 2.83E-02 4.35E-03 6.10E-01 7.57E-03 1.24E-02 2.35E-03

rs4971648 NRXN1 A/G 1.22 [1.10-1.34] 9.67E-05 (1.25E-04)

4.42E-05 (5.94E-05)

1.21 [1.10-1.34] 1.77E-04 3.99E-03 1.22E-02 8.12E-01 4.71E-02 1.48E-03 1.56E-03

rs10181805 ACVR2A A/C 1.28 [1.13-1.45] 8.50E-05 (1.10E-04)

7.68E-05 (1.01E-04)

1.28 [1.14-1.45] 7.08E-05 2.09E-01 1.21E-05 2.78E-02 3.01E-03 8.79E-03 1.74E-03

rs1405213 MMADHC A/G 1.22 [1.11-1.35] 7.17E-05 (9.32E-05)

2.93E-05 (3.99E-05)

1.23 [1.11-1.36] 4.69E-05 1.44E-02 7.68E-04 5.27E-01 3.07E-03 4.77E-03 4.73E-03

rs7597915 CACNB4 G/A 1.30 [1.14-1.48] 9.30E-05 (1.20E-04)

3.74E-05 (5.06E-05)

1.29 [1.14-1.47] 1.31E-04 1.12E-02 3.36E-03 9.07E-01 4.13E-01 9.41E-06 2.62E-03

rs236833 PARD3B A/C 1.23 [1.10-1.37] 2.17E-04 (2.72E-04)

5.99E-04 (7.41E-04)

1.22 [1.09-1.36] 3.83E-04 2.95E-03 3.28E-02 5.24E-01 1.22E-01 3.03E-04 6.86E-03

rs207851 MARCH4 C/T 1.17 [1.07-1.29] 9.19E-04 (1.11E-03)

1.87E-04 (2.40E-04)

1.17 [1.07-1.29] 9.58E-04 6.84E-01 2.16E-05 6.40E-03 1.09E-02 2.61E-02 4.02E-04

rs2574720 VGLL4 T/G 1.20 [1.10-1.32] 1.03E-04 (1.33E-04)

4.07E-05 (5.49E-05)

1.20 [1.10-1.32] 1.24E-04 4.10E-03 8.63E-03 8.28E-01 8.21E-03 7.51E-03 7.90E-04

SUPPLEMENTARY DATA


rs2070478 ITGA9 C/T 1.22 [1.10-1.36] 1.86E-04 (2.35E-04)

1.77E-04 (2.28E-04)

1.22 [1.10-1.35] 2.82E-04 4.36E-03 1.83E-02 7.37E-01 2.09E-02 4.95E-03 1.78E-02

rs2322272 RYBP T/C 1.34 [1.16-1.55] 7.04E-05 (9.15E-05)

9.13E-05 (1.20E-04)

1.33 [1.15-1.53] 1.39E-04 1.03E-03 2.82E-02 4.60E-01 4.82E-03 7.41E-03 9.26E-04

rs867829 ZIC4 C/T 1.24 [1.11-1.39] 1.63E-04 (2.06E-04)

9.23E-05 (1.21E-04)

1.24 [1.11-1.39] 1.88E-04 2.74E-03 1.80E-02 6.56E-01 3.53E-04 7.27E-02 9.77E-03

rs4364195 FNDC3B G/A 1.23 [1.12-1.35] 1.47E-05 (2.00E-05)

5.12E-05 (6.85E-05)

1.23 [1.12-1.35] 1.81E-05 2.30E-02 1.25E-04 2.79E-01 3.54E-02 8.04E-05 2.47E-02

rs4894535 FNDC3B T/C 1.23 [1.12-1.36] 3.65E-05 (4.84E-05)

4.17E-05 (5.62E-05)

1.23 [1.11-1.36] 5.08E-05 5.60E-03 2.46E-03 8.35E-01 2.07E-02 4.72E-04 1.21E-02

rs6445073 NCEH1 A/G 1.20 [1.08-1.33] 7.56E-04 (9.16E-04)

2.70E-03 (3.18E-03)

1.20 [1.08-1.33] 6.41E-04 2.63E-02 7.83E-03 7.76E-01 2.22E-02 8.13E-03 3.43E-03

rs1316686 CPEB2 A/G 1.23 [1.11-1.37] 5.71E-05 (7.47E-05)

9.55E-05 (1.25E-04)

1.23 [1.11-1.36] 8.79E-05 6.48E-04 2.58E-02 3.48E-01 3.91E-03 7.59E-03 5.45E-02

rs13120537 ARAP2 C/T 1.38 [1.17-1.62] 1.34E-04 (1.71E-04)

9.92E-05 (1.30E-04)

1.38 [1.18-1.63] 1.01E-04 7.37E-04 2.69E-02 2.85E-01 7.76E-03 6.00E-03 6.75E-05

rs17640893 COX7B2 G/A 1.52 [1.28-1.80] 2.09E-06 (3.02E-06)

3.51E-06 (5.12E-06)

1.51 [1.27-1.79] 4.39E-06 1.41E-05 2.30E-02 1.71E-01 1.30E-03 8.31E-04 8.61E-05

rs17598636 COX7B2 T/C 1.52 [1.28-1.81] 1.71E-06 (2.49E-06)

2.86E-06 (4.20E-06)

1.51 [1.27-1.80] 3.73E-06 1.62E-05 1.88E-02 1.95E-01 1.31E-03 7.29E-04 9.04E-05

rs7658410 GABRA4 C/T 1.41 [1.18-1.67] 9.79E-05 (1.26E-04)

1.51E-04 (1.95E-04)

1.40 [1.18-1.66] 1.63E-04 7.78E-04 3.91E-02 3.94E-01 7.65E-03 8.11E-03 1.06E-03

rs12643813 FSTL5 G/A 1.21 [1.10-1.34] 1.67E-04 (2.12E-04)

1.11E-04 (1.45E-04)

1.21 [1.10-1.34] 1.70E-04 1.18E-03 3.03E-02 4.46E-01 5.74E-03 1.38E-02 3.23E-03

rs1565469 GALNTL6 A/G 1.21 [1.10-1.33] 1.25E-04 (1.60E-04)

1.60E-04 (2.07E-04)

1.21 [1.10-1.33] 1.15E-04 8.13E-04 2.80E-02 3.92E-01 1.38E-01 1.82E-04 1.18E-02

rs7722385 MYO10 C/T 1.28 [1.13-1.46] 1.71E-04 (2.16E-04)

5.18E-04 (6.44E-04)

1.28 [1.12-1.45] 2.20E-04 2.04E-03 2.60E-02 5.17E-01 1.83E-02 8.51E-03 2.57E-05

rs10052705 EFNA5 A/G 1.20 [1.08-1.33] 5.61E-04 (6.86E-04)

2.09E-04 (2.67E-04)

1.21 [1.09-1.34] 3.57E-04 3.83E-02 2.51E-03 4.80E-01 5.21E-02 1.04E-03 1.72E-02

rs3853477 SPRY4 T/C 1.26 [1.12-1.41] 1.24E-04 (1.58E-04)

1.42E-04 (1.84E-04)

1.27 [1.13-1.42] 9.35E-05 1.18E-03 1.80E-02 5.16E-01 2.63E-02 1.55E-03 1.05E-04

rs10261234 TMEM106B A/G 1.25 [1.12-1.40] 6.55E-05 (8.53E-05)

5.21E-05 (6.97E-05)

1.25 [1.12-1.40] 9.48E-05 6.43E-04 2.77E-02 3.97E-01 4.34E-02 1.65E-04 2.77E-03

rs12536822 TMEM106B A/G 1.23 [1.10-1.38] 2.06E-04 (2.60E-04)

1.23E-04 (1.60E-04)

1.24 [1.11-1.38] 2.17E-04 1.43E-02 4.51E-03 7.75E-01 2.45E-01 5.71E-05 2.68E-03

rs1117750 DGKB C/T 1.19 [1.07-1.32] 1.16E-03 (1.39E-03)

2.05E-03 (2.44E-03)

1.19 [1.07-1.32] 1.60E-03 1.94E-02 2.89E-02 9.27E-01 9.51E-02 4.94E-03 1.85E-03

rs17544225 GRB10 C/T 1.34 [1.15-1.55] 1.72E-04 (2.18E-04)

1.11E-04 (1.45E-04)

1.33 [1.15-1.55] 2.32E-04 1.01E-02 7.10E-03 8.74E-01 1.60E-01 1.10E-04 2.71E-04

SUPPLEMENTARY DATA


rs1442244 POM121L12 A/G 1.20 [1.09-1.32] 2.84E-04 (3.54E-04)

4.16E-04 (5.20E-04)

1.20 [1.09-1.32] 3.55E-04 2.06E-03 4.01E-02 4.60E-01 2.40E-04 1.32E-01 1.58E-04

rs10277213 CLDN12 A/G 1.34 [1.15-1.56] 2.25E-04 (2.83E-04)

1.17E-04 (1.53E-04)

1.34 [1.15-1.57] 2.07E-04 1.98E-03 2.52E-02 4.75E-01 1.83E-01 8.79E-05 2.24E-03

rs13236754 ZNF398 G/A 1.33 [1.14-1.55] 2.94E-04 (3.67E-04)

1.60E-04 (2.07E-04)

1.31 [1.13-1.53] 5.27E-04 6.28E-02 2.10E-03 3.71E-01 8.70E-02 1.46E-03 1.64E-03

rs4732948 DUSP4 G/A 1.29 [1.13-1.46] 1.04E-04 (1.34E-04)

9.08E-05 (1.19E-04)

1.29 [1.14-1.47] 1.13E-04 7.95E-05 1.04E-01 9.43E-02 4.64E-02 4.90E-04 1.60E-02

rs6983230 ARMC1 G/A 1.22 [1.10-1.34] 9.74E-05 (1.25E-04)

1.06E-04 (1.39E-04)

1.22 [1.10-1.34] 9.96E-05 2.61E-03 1.01E-02 7.30E-01 1.46E-02 7.85E-04 9.52E-04

rs7833031 PDE7A A/G 1.20 [1.09-1.32] 1.79E-04 (2.26E-04)

1.57E-04 (2.03E-04)

1.20 [1.09-1.32] 2.24E-04 2.38E-03 2.37E-02 5.47E-01 1.25E-02 3.04E-03 5.51E-04

rs10808374 GRHL2 T/G 1.23 [1.11-1.36] 6.08E-05 (7.94E-05)

6.87E-05 (9.11E-05)

1.22 [1.10-1.35] 1.24E-04 5.69E-03 6.20E-03 9.62E-01 2.88E-02 8.84E-04 2.10E-04

rs13266634 SLC30A8 C/T 1.18 [1.07-1.30] 9.08E-04 (1.09E-03)

4.42E-04 (5.52E-04)

1.18 [1.07-1.29] 1.10E-03 5.23E-02 6.58E-03 6.13E-01 1.53E-02 3.33E-02 4.91E-02

rs7386204 TSNARE1 A/G 1.25 [1.13-1.37] 1.07E-05 (1.47E-05)

5.42E-05 (7.24E-05)

1.24 [1.13-1.37] 1.76E-05 8.35E-04 4.82E-03 7.06E-01 5.39E-03 1.07E-03 1.22E-03

rs600951 DOCK8 C/T 1.24 [1.12-1.37] 5.72E-05 (7.48E-05)

6.04E-05 (8.04E-05)

1.23 [1.11-1.37] 7.58E-05 1.32E-01 3.93E-05 6.24E-02 8.07E-03 9.87E-04 7.62E-04

rs10814916 GLIS3 C/A 1.15 [1.05-1.27] 3.42E-03 (3.96E-03)

1.01E-03 (1.23E-03)

1.15 [1.04-1.26] 4.15E-03 3.99E-01 1.29E-03 9.09E-02 3.69E-02 5.71E-02 1.11E-03

rs2383208 CDKN2B A/G 1.32 [1.20-1.46] 1.46E-08 (2.45E-08)

4.00E-09 (7.28E-09)

1.33 [1.20-1.46] 1.15E-08 1.81E-03 5.22E-07 1.63E-01 2.09E-03 7.90E-07 1.68E-07

rs668498 FBXO18 T/C 1.24 [1.12-1.38] 4.46E-05 (5.88E-05)

2.60E-05 (3.56E-05)

1.24 [1.12-1.37] 5.59E-05 7.25E-02 8.65E-05 1.29E-01 6.06E-03 2.53E-03 1.98E-03

rs11257655 CDC123 T/C 1.24 [1.13-1.37] 1.05E-05 (1.45E-05)

2.10E-05 (2.89E-05)

1.24 [1.13-1.37] 1.30E-05 8.29E-04 3.61E-03 7.16E-01 1.76E-02 1.65E-04 9.18E-05

rs5015480 HHEX C/T 1.24 [1.10-1.40] 5.14E-04 (6.30E-04)

4.45E-04 (5.56E-04)

1.25 [1.11-1.41] 3.31E-04 7.10E-03 1.42E-02 8.15E-01 6.89E-03 1.03E-02 1.87E-02

rs11188904 PIK3AP1 A/G 1.20 [1.09-1.32] 1.38E-04 (1.76E-04)

1.82E-04 (2.34E-04)

1.21 [1.10-1.33] 1.05E-04 4.29E-03 7.01E-03 8.98E-01 2.38E-02 3.41E-03 2.14E-03

rs10886471 GRK5 C/T 1.29 [1.15-1.45] 1.48E-05 (2.02E-05)

2.86E-05 (3.90E-05)

1.28 [1.14-1.44] 3.49E-05 3.45E-02 1.56E-04 2.70E-01 5.53E-02 7.13E-05 1.99E-04

rs718948 CTBP2 T/C 1.23 [1.10-1.38] 2.72E-04 (3.40E-04)

2.73E-04 (3.46E-04)

1.23 [1.10-1.37] 3.91E-04 1.37E-02 9.01E-03 9.60E-01 6.67E-05 1.98E-01 2.35E-04

rs11827207 KCNQ1 G/A 1.30 [1.12-1.51] 5.80E-04 (7.09E-04)

6.58E-04 (8.12E-04)

1.30 [1.12-1.51] 5.89E-04 2.16E-02 8.82E-03 9.76E-01 2.16E-02 6.32E-03 8.11E-03

rs3781683 CAPN5 T/C 1.36 [1.14-1.62] 5.67E-04 (6.93E-04)

7.87E-04 (9.66E-04)

1.37 [1.15-1.63] 5.02E-04 1.01E-01 9.21E-04 2.23E-01 4.27E-03 2.78E-02 4.23E-02

SUPPLEMENTARY DATA


rs495966 ODZ4 C/T 1.23 [1.12-1.36] 2.71E-05 (3.63E-05)

4.31E-05 (5.80E-05)

1.22 [1.11-1.35] 4.70E-05 5.89E-03 2.11E-03 8.49E-01 3.36E-02 1.96E-04 2.95E-04

rs1472401 FAM181B T/C 1.29 [1.12-1.48] 3.51E-04 (4.35E-04)

2.54E-04 (3.22E-04)

1.29 [1.13-1.49] 3.19E-04 2.88E-03 2.86E-02 6.66E-01 7.40E-03 1.69E-02 3.64E-02

rs4559795 LHFP G/T 1.38 [1.16-1.63] 2.18E-04 (2.74E-04)

3.84E-04 (4.81E-04)

1.39 [1.17-1.64] 1.80E-04 6.37E-03 8.38E-03 9.19E-01 1.20E-03 3.96E-02 1.50E-03

rs4620862 SPERT T/C 1.26 [1.12-1.42] 1.21E-04 (1.55E-04)

6.20E-05 (8.25E-05)

1.26 [1.11-1.41] 2.14E-04 1.11E-01 2.50E-04 1.67E-01 8.71E-02 4.31E-04 9.15E-05

rs7336343 DACH1 T/C 1.23 [1.09-1.39] 6.15E-04 (7.50E-04)

3.63E-04 (4.56E-04)

1.23 [1.10-1.39] 6.08E-04 9.80E-03 1.97E-02 8.33E-01 1.05E-03 9.28E-02 5.52E-03

rs12589387 FLRT2 T/C 1.20 [1.09-1.32] 1.70E-04 (2.15E-04)

3.37E-04 (4.25E-04)

1.20 [1.09-1.32] 1.85E-04 9.21E-03 6.18E-03 9.10E-01 4.30E-03 1.96E-02 7.24E-04

rs4391997 CALM1 A/G 1.27 [1.12-1.43] 2.23E-04 (2.80E-04)

7.44E-05 (9.84E-05)

1.26 [1.12-1.43] 2.53E-04 9.08E-05 1.69E-01 5.42E-02 3.87E-03 1.86E-02 6.40E-04

rs1768111 GSC A/G 1.34 [1.17-1.53] 2.01E-05 (2.71E-05)

1.97E-05 (2.72E-05)

1.35 [1.18-1.54] 1.99E-05 2.28E-04 1.43E-02 3.70E-01 4.41E-03 3.03E-03 1.37E-04

rs234146 AL163872.1 T/C 1.33 [1.15-1.54] 9.56E-05 (1.23E-04)

1.48E-04 (1.92E-04)

1.33 [1.15-1.54] 1.19E-04 2.70E-01 1.39E-05 2.31E-02 7.95E-03 4.93E-03 4.15E-07

rs2873027 GABRB3 G/A 1.24 [1.10-1.40] 4.92E-04 (6.04E-04)

4.73E-04 (5.90E-04)

1.24 [1.10-1.40] 6.52E-04 2.54E-02 8.32E-03 8.33E-01 1.78E-02 9.35E-03 4.03E-04

rs8030388 SPRED1 C/T 1.26 [1.12-1.43] 2.36E-04 (2.96E-04)

6.11E-04 (7.56E-04)

1.26 [1.11-1.43] 3.04E-04 4.14E-04 9.31E-02 1.79E-01 3.99E-02 1.72E-03 4.30E-02

rs7403531 RASGRP1 T/C 1.21 [1.10-1.34] 1.55E-04 (1.97E-04)

1.17E-04 (1.53E-04)

1.21 [1.09-1.33] 2.15E-04 1.95E-04 1.06E-01 1.19E-01 4.31E-03 2.60E-02 7.15E-03

rs7172432 C2CD4A A/G 1.18 [1.07-1.30] 8.08E-04 (9.77E-04)

2.85E-04 (3.62E-04)

1.18 [1.07-1.30] 7.15E-04 5.88E-03 3.54E-02 6.27E-01 5.64E-03 3.19E-02 3.94E-02

rs10519219 MORF4L1 T/C 1.20 [1.08-1.32] 4.99E-04 (6.12E-04)

2.42E-04 (3.08E-04)

1.19 [1.08-1.32] 7.89E-04 1.14E-03 1.13E-01 2.09E-01 1.07E-02 2.45E-02 3.86E-03

rs3862435 CRTC3 A/G 1.28 [1.13-1.45] 1.00E-04 (1.29E-04)

1.30E-04 (1.69E-04)

1.28 [1.13-1.45] 1.49E-04 1.37E-02 3.12E-03 6.86E-01 7.95E-02 5.46E-04 2.42E-04

rs4566137 CRTC3 A/G 1.26 [1.12-1.42] 1.08E-04 (1.38E-04)

2.11E-04 (2.70E-04)

1.24 [1.11-1.40] 2.54E-04 3.12E-02 2.17E-03 5.07E-01 2.67E-01 1.18E-04 1.24E-03

rs1346491 CPPED1 C/T 1.25 [1.12-1.39] 3.97E-05 (5.25E-05)

2.66E-05 (3.64E-05)

1.25 [1.12-1.38] 5.24E-05 1.57E-02 7.84E-04 5.19E-01 3.02E-02 2.78E-04 1.31E-04

rs7184792 CPPED1 A/G 1.22 [1.11-1.35] 7.34E-05 (9.53E-05)

2.96E-05 (4.03E-05)

1.22 [1.10-1.34] 1.07E-04 8.54E-02 1.52E-04 1.39E-01 1.06E-02 2.56E-03 5.58E-05

rs4785345 ZNF423 C/T 1.28 [1.14-1.43] 1.87E-05 (2.53E-05)

6.82E-06 (9.74E-06)

1.28 [1.14-1.43] 2.46E-05 3.12E-01 7.25E-07 5.07E-03 6.31E-04 1.36E-02 1.49E-04

rs7199979 ZNF423 C/T 1.29 [1.16-1.44] 3.50E-06 (4.98E-06)

1.10E-06 (1.67E-06)

1.29 [1.16-1.44] 4.67E-06 1.30E-01 6.43E-07 1.44E-02 1.15E-04 9.70E-03 1.60E-05

SUPPLEMENTARY DATA


rs17258832 LOC388276 A/C 1.34 [1.15-1.55] 1.86E-04 (2.35E-04)

1.31E-04 (1.70E-04)

1.34 [1.15-1.56] 1.81E-04 8.63E-03 6.17E-03 9.50E-01 2.30E-02 1.49E-03 5.33E-03

rs2221746 G/A 1.25 [1.13-1.39] 1.20E-05 (1.65E-05)

1.83E-05 (2.53E-05)

1.26 [1.14-1.40] 7.71E-06 6.65E-04 2.61E-03 7.43E-01 1.14E-04 1.43E-02 1.08E-04

rs6564447 ADAMTS18 G/A 1.22 [1.11-1.35] 1.03E-04 (1.33E-04)

1.18E-04 (1.53E-04)

1.22 [1.10-1.35] 1.51E-04 1.13E-03 2.84E-02 4.52E-01 1.55E-02 2.88E-03 6.59E-04

rs11651010 DNAH9 C/T 1.30 [1.13-1.49] 2.92E-04 (3.64E-04)

3.10E-04 (3.91E-04)

1.29 [1.12-1.48] 4.00E-04 2.29E-02 5.37E-03 7.88E-01 2.32E-01 1.34E-04 4.63E-04

rs4430796 HNF1B G/A 1.27 [1.15-1.41] 4.83E-06 (6.81E-06)

1.26E-06 (1.90E-06)

1.28 [1.15-1.42] 4.93E-06 5.74E-04 1.88E-03 7.62E-01 2.04E-03 1.46E-03 1.79E-04

rs4795223 HNF1B C/T 1.25 [1.14-1.38] 6.63E-06 (9.25E-06)

6.82E-06 (9.74E-06)

1.24 [1.13-1.37] 1.62E-05 6.48E-02 1.88E-05 9.82E-02 2.63E-03 3.79E-03 2.09E-05

rs1106701 PTPRM C/T 1.37 [1.17-1.61] 1.21E-04 (1.55E-04)

5.61E-05 (7.49E-05)

1.37 [1.17-1.61] 1.59E-04 2.12E-03 1.86E-02 6.29E-01 4.05E-04 7.12E-02 1.04E-03

rs4798615 PTPRM G/A 1.36 [1.17-1.57] 4.24E-05 (5.60E-05)

2.33E-05 (3.20E-05)

1.36 [1.17-1.57] 5.51E-05 2.18E-03 6.53E-03 7.87E-01 7.18E-04 2.07E-02 2.23E-04

rs12609246 RASGRP4 G/A 1.19 [1.08-1.31] 3.63E-04 (4.49E-04)

2.82E-04 (3.58E-04)

1.19 [1.08-1.31] 6.14E-04 1.66E-02 1.21E-02 8.93E-01 2.02E-02 9.98E-03 2.27E-03

rs4802887 LGALS4 T/G 1.29 [1.16-1.43] 2.07E-06 (2.99E-06)

9.82E-07 (1.49E-06)

1.27 [1.15-1.41] 6.08E-06 4.97E-03 2.59E-04 6.61E-01 1.40E-03 6.06E-04 1.62E-05

rs1078734 ECH1 T/C 1.25 [1.13-1.39] 2.80E-05 (3.74E-05)

2.03E-05 (2.80E-05)

1.25 [1.12-1.39] 4.27E-05 1.65E-03 6.59E-03 6.46E-01 6.47E-04 9.79E-03 4.86E-04

rs2569491 KLK14 A/G 1.35 [1.15-1.58] 2.57E-04 (3.22E-04)

2.65E-04 (3.36E-04)

1.34 [1.15-1.58] 3.06E-04 8.55E-03 1.10E-02 9.45E-01 1.20E-02 9.34E-03 4.19E-03

rs2424155 ZNF133 T/C 1.20 [1.09-1.33] 1.74E-04 (2.20E-04)

2.37E-04 (3.02E-04)

1.20 [1.09-1.33] 1.70E-04 2.74E-02 1.57E-03 5.05E-01 4.55E-01 1.40E-05 3.99E-04

rs11696113 BPIL1 T/C 1.29 [1.12-1.49] 3.40E-04 (4.22E-04)

4.16E-04 (5.21E-04)

1.29 [1.12-1.49] 3.77E-04 1.12E-03 6.19E-02 2.99E-01 2.74E-02 5.58E-03 9.42E-04

rs1489734 LOC100505973 C/T 1.21 [1.10-1.34] 8.79E-05 (1.14E-04)

4.93E-05 (6.61E-05)

1.21 [1.10-1.33] 1.28E-04 1.02E-02 3.64E-03 8.60E-01 1.45E-02 2.73E-03 1.59E-02

rs196094 KCNJ4 A/G 1.27 [1.13-1.43] 8.32E-05 (1.08E-04)

2.16E-04 (2.76E-04)

1.27 [1.13-1.43] 1.25E-04 8.57E-06 2.69E-01 1.77E-02 2.24E-03 7.58E-03 1.86E-03

rs1026162 HDHD1 C/T 1.37 [1.20-1.56] 1.53E-06 (2.23E-06)

3.16E-06 (4.63E-06)

1.37 [1.21-1.56] 2.15E-06 9.01E-05 3.84E-03 5.25E-01 3.52E-04 1.60E-03 1.48E-03

rs12010175 FAM58A G/A 1.30 [1.18-1.44] 2.03E-07 (3.15E-07)

4.47E-08 (7.52E-08)

1.30 [1.18-1.44] 2.25E-07 3.20E-04 1.37E-04 8.51E-01 6.50E-06 7.44E-03 9.38E-05

rs5945326 DUSP9 A/G 1.28 [1.18-1.39] 7.02E-09 (1.21E-08)

4.24E-09 (7.70E-09)

1.27 [1.17-1.38] 1.60E-08 1.97E-05 1.27E-04 7.36E-01 2.72E-07 6.02E-03 8.97E-05

Pooled analyses: samples from Shanghai and from Beijing were pooled for the primary association analyses, adjusting for the first two principle components. Secondary analyses: analyses stratified by geographical regions (Beijing and Shanghai), or by sex, or between cases with T2D family history and non-diabetic

SUPPLEMENTARY DATA


controls. * P values corrected for genomic control are presented in parentheses. † P values in Shanghai and Beijing subpopulations were corrected for genomic control before fixed-effect meta-analyses. ‡ The associations and ORs of each SNP with T2D were further adjusted for BMI. R/A: Risk allele/Alternative allele, RAF: Risk allele frequency, OR: odds ratio for the risk allele.

Supplementary Table 3. Associations with T2D for previously reported T2D SNPs in stage 1

SNP CHR Risk allele

Reported gene

Reported Population

Reference Reported OR [95% CI]

Stage 1

Methods RAF (cases)

RAF (controls)

OR [95% CI] P P hetero *

rs10923931 1 T NOTCH2, ADAM30 EU (7) 1.13 [1.08-1.17] imputed 0.030 0.029 1.01 [0.76-1.33] 9.68E-01 4.17E-01

rs340874 1 C PROX1 EU (8) 1.07 [1.05–1.09] genotyped 0.380 0.374 1.03 [0.93-1.14] 5.65E-01 4.42E-01

rs780094 2 C GCKR EU (8) 1.06 [1.04–1.08] genotyped 0.475 0.444 1.14 [1.04-1.26] 6.11E-03 1.28E-01

rs7578597 2 T THADA EU (8) 1.15 [1.10-1.20] NA NA NA NA [NA-NA] NA NA

rs243021 2 A BCL11A EU (9) 1.08 [1.06-1.10] genotyped 0.688 0.679 1.05 [0.95-1.16] 3.12E-01 6.27E-01

rs7593730 2 C RBMS1, ITGB6 EU (10) 1.11 [1.08-1.16] imputed 0.831 0.840 0.95 [0.84-1.08] 4.50E-01 2.28E-02

rs3923113 2 A GRB14 SA (11) 1.09 [1.06-1.13] genotyped 0.872 0.855 1.14 [1.00-1.31] 5.78E-02 5.17E-01

rs2943641 2 C IRS1 EU (12) 1.19 [1.13-1.25] genotyped 0.934 0.931 1.14 [0.94-1.38] 1.75E-01 6.59E-01

rs1801282 3 C PPARG EU (13) 1.14 [1.08-1.20] imputed 0.946 0.935 1.25 [1.03-1.52] 2.68E-02 3.77E-01

rs7612463 3 C UBE2E2 EA (14) 1.15 [1.08-1.14] genotyped 0.812 0.785 1.19 [1.06-1.34] 4.07E-03 6.06E-01

rs831571 3 C PSMD6 EA (6) 1.09 [1.06–1.12] genotyped 0.658 0.641 1.09 [0.99-1.20] 9.54E-02 9.58E-01

rs4607103 3 C ADAMTS9 EU (7) 1.09 [1.06-1.12] imputed 0.633 0.612 1.11 [1.01-1.23] 3.41E-02 7.01E-01

rs11708067 3 A ADCY5 EU (8) 1.12 [1.09–1.15] NA NA NA NA [NA-NA] NA NA

rs1470579 3 C IGF2BP2 EU (9) 1.14 [1.09-1.19] genotyped 0.280 0.253 1.16 [1.04-1.29] 6.51E-03 7.88E-01

rs16861329 3 G ST6GAL1 SA (11) 1.09 [1.06-1.12] genotyped 0.829 0.812 1.14 [1.01-1.29] 3.72E-02 4.80E-01

rs6815464 4 C MAEA EA (6) 1.13 [1.10–1.16] imputed 0.590 0.566 1.13 [1.02-1.24] 1.47E-02 9.72E-01

rs10010131 4 G WFS1 EU (15) 1.11 [1.05-1.16] imputed 0.960 0.953 1.24 [0.98-1.57] 7.20E-02 3.67E-01

rs4457053 5 G ZBED3 EU (9) 1.08 [1.06-1.11] imputed 0.044 0.042 1.04 [0.82-1.32] 7.64E-01 7.48E-01

rs7754840 6 C CDKAL1 EU (16) 1.12 [1.08-1.16] genotyped 0.475 0.411 1.35 [1.23-1.48] 6.78E-10 3.33E-04

rs9470794 6 C ZFAND3 EA (11) 1.12 [1.08–1.16] genotyped 0.318 0.298 1.10 [1.00-1.22] 6.30E-02 7.56E-01

SUPPLEMENTARY DATA


rs1535500 6 T KCNK16 EA (11) 1.08 [1.05–1.11] imputed 0.476 0.460 1.08 [0.98-1.19] 1.14E-01 9.85E-01

rs9472138 6 T VEGFA EU (7) 1.06 [1.04-1.09] genotyped 0.113 0.098 1.16 [1.00-1.36] 5.16E-02 2.37E-01

rs2191349 7 T DGKB, TMEM195 EU (8) 1.06 [1.04–1.08] imputed 0.650 0.629 1.08 [0.98-1.19] 1.49E-01 7.71E-01

rs864745 7 T JAZF1 EU (7) 1.10 [1.07-1.13] imputed 0.783 0.756 1.16 [1.04-1.30] 9.31E-03 3.56E-01

rs4607517 7 A GCK EU (8) 1.07 [1.05–1.10] genotyped 0.217 0.209 1.06 [0.95-1.19] 3.15E-01 8.75E-01

rs6467136 7 G GCC1, PAX4 EA (6) 1.11 [1.07–1.14] genotyped 0.791 0.785 1.03 [0.92-1.15] 6.58E-01 1.91E-01

rs972283 7 G KLF14 EU (9) 1.07 [1.05-1.10] imputed 0.738 0.730 1.04 [0.93-1.16] 4.76E-01 6.36E-01

rs896854 8 T TP53INP1 EU (9) 1.06 [1.04-1.09] genotyped 0.348 0.337 1.07 [0.97-1.18] 1.82E-01 8.57E-01

rs13266634 8 C SLC30A8 EU (17) 1.15 [1.12-1.19] genotyped 0.609 0.570 1.18 [1.07-1.29] 9.08E-04 6.63E-01

rs7041847 9 A GLIS3 EA (11) 1.10 [1.07–1.13] genotyped 0.475 0.449 1.14 [1.04-1.25] 7.57E-03 5.09E-01

rs17584499 9 T PTPRD EA (18) 1.57 [1.36-1.82] genotyped 0.090 0.090 1.01 [0.85-1.19] 9.43E-01 6.81E-05

rs10811661 9 T CDKN2A, CDKN2B EU (16) 1.20 [1.12-1.28] imputed 0.605 0.541 1.33 [1.20-1.47] 2.04E-08 9.67E-02

rs13292136 9 C CHCHD9 EU (9) 1.11 [1.07-1.15] imputed 0.917 0.911 1.11 [0.94-1.31] 2.43E-01 9.59E-01

rs10906115 10 A CDC123, CAMK1D EA (19) 1.13 [1.08-1.18] genotyped 0.651 0.610 1.22 [1.10-1.34] 9.86E-05 1.87E-01

rs1802295 10 A VPS26A SA (11) 1.08 [1.05-1.12] genotyped 0.105 0.107 0.98 [0.84-1.15] 7.99E-01 2.32E-01

rs5015480 10 C HHEX EU (13) 1.13 [1.07-1.19] genotyped 0.203 0.171 1.24 [1.10-1.40] 5.14E-04 1.75E-01

rs7903146 10 T TCF7L2 EU (17) 1.65 [1.28, 2.02] genotyped 0.047 0.037 1.25 [0.99-1.58] 6.57E-02 9.67E-02

rs231362 11 G KCNQ1 EU (9) 1.08 [1.06-1.10] imputed 0.887 0.858 1.27 [1.10-1.47] 1.04E-03 2.72E-02

rs2237892 11 C KCNQ1 EA (20) 1.40 [1.34-1.47] genotyped 0.719 0.657 1.32 [1.19-1.46] 1.39E-07 2.80E-01

rs5215 11 C KCNJ11 EU (13) 1.14 [1.10-1.19] genotyped 0.419 0.407 1.08 [0.98-1.19] 1.19E-01 2.97E-01

rs1552224 11 A CENTD2 EU (9) 1.14 [1.11-1.17] genotyped 0.924 0.916 1.12 [0.94-1.33] 2.10E-01 8.11E-01

rs1387153 11 T MTNR1B EU (9) 1.09 [1.06-1.11] genotyped 0.415 0.391 1.12 [1.02-1.23] 2.26E-02 6.15E-01

rs1531343 12 C HMGA2 EU (9) 1.10 [1.07-1.14] imputed 0.877 0.877 1.03 [0.89-1.18] 7.39E-01 3.49E-01

rs7961581 12 C TSPAN8, LGR5 EU (7) 1.09 [1.06-1.12] imputed 0.225 0.211 1.07 [0.95-1.20] 2.76E-01 7.26E-01

rs7957197 12 T HNF1A EU (9) 1.07 [1.05-1.10] NA NA NA NA [NA-NA] NA NA

rs1359790 13 G SPRY2 EA (19) 1.15 [1.10-1.20] imputed 0.727 0.715 1.06 [0.96-1.18] 2.67E-01 1.65E-01

SUPPLEMENTARY DATA


rs7172432 15 A C2CD4A, C2CD4B EA (14) 1.11 [1.08-1.14] genotyped 0.621 0.584 1.18 [1.07-1.30] 8.08E-04 2.43E-01

rs7178572 15 G HMG20A SA (11) 1.09 [1.06-1.12] genotyped 0.376 0.356 1.10 [1.00-1.21] 6.11E-02 8.75E-01

rs11634397 15 G ZFAND6 EU (9) 1.06 [1.04-1.08] imputed 0.084 0.090 0.91 [0.76-1.08] 2.86E-01 8.74E-02

rs2028299 15 C AP3S2 SA (11) 1.10 [1.07-1.13] genotyped 0.200 0.193 1.05 [0.93-1.18] 4.35E-01 4.46E-01

rs8042680 15 A PRC1 EU (9) 1.07 [1.05-1.09] genotyped 0.993 0.986 2.20 [1.34-3.62] 1.98E-03 4.73E-03

rs9939609 16 A FTO EU (21) 1.15 [1.09-1.23] imputed 0.130 0.112 1.17 [1.01-1.35] 3.51E-02 8.54E-01

rs391300 17 G SRR EA (18) 1.28 [1.18-1.39] genotyped 0.707 0.704 1.00 [0.90-1.11] 9.60E-01 1.92E-04

rs4430796 17 G HNF1B EU (9) 1.14 [1.08-1.20] genotyped 0.328 0.280 1.27 [1.15-1.41] 4.83E-06 6.15E-02

rs3786897 19 A PEPD EA (11) 1.10 [1.07–1.14] imputed 0.536 0.517 1.08 [0.98-1.19] 1.13E-01 7.35E-01

rs6017317 20 G FITM2, R3HDML, HNF4A

EA (11) 1.09 [1.07–1.12] imputed 0.453 0.420 1.17 [1.07-1.29] 1.20E-03 1.48E-01

rs4812829 20 A HNF4A SA (11) 1.09 [1.06-1.12] genotyped 0.447 0.428 1.09 [0.99-1.20] 7.34E-02 9.71E-01

rs5945326 X A DUSP9 EU (9) 1.27 [1.18-1.37] genotyped 0.657 0.591 1.28 [1.18-1.39] 7.02E-09 9.34E-01

The associations of each SNP with T2D were not adjusted for BMI. * P for heterogeneity of ORs between the stage 1 and the previously reported. R/A: Risk allele/Alternative allele. RAF: Risk allele frequency. Reported population: EU for Europe, SA for South Asia, EA for East Asia. NA: not available.

SUPPLEMENTARY DATA


Supplementary Table 4. SNP selection in each genomic region for replication in stage 2

CHR Replicated SNPs Index SNP Proxy SNPs

Position (bp) P * P BMI * r2 †

1 rs10915140 rs10915140 rs2133041 30,757,250 4.99E-04 4.44E-04 0.97 rs10915140 30,758,238 1.62E-04 1.65E-04 - 1 rs4949302 rs4949302 rs4949302 31,033,624 8.25E-05 3.51E-05 - rs1407891 31,067,354 1.10E-03 5.89E-04 0.31 1 rs1134767 rs1134767 rs1134767 62,228,602 4.13E-05 2.98E-05 - rs12728194 62,230,375 4.15E-04 2.45E-04 0.94 1 rs1984285 rs1984285 rs1984285 153,063,519 8.03E-04 1.48E-03 - 1 rs4656256,

rs4656902 rs4656256 rs4656899 158,570,790 5.56E-04 1.62E-04 0.13

rs10494342 158,583,744 8.18E-04 2.54E-04 0.13 rs4656256 158,597,643 1.86E-04 5.99E-05 - rs4656902 158,600,366 1.44E-04 6.15E-05 0.24 1 rs12563833 rs12563833 rs2072041 173,359,463 6.58E-04 6.09E-04 0.67 rs12146041 173,368,784 7.84E-04 4.90E-04 0.83 rs4651322 173,371,342 4.80E-04 4.14E-04 0.69 rs2072038 173,372,401 6.61E-04 1.19E-03 0.22 rs12563833 173,376,140 8.25E-05 5.41E-05 - rs1018829 173,376,345 5.76E-04 5.69E-04 0.74 rs1012466 173,376,507 4.58E-04 7.88E-04 0.22 1 rs924569 rs924569 rs12750795 209,143,352 5.23E-04 8.47E-04 0.93 rs17017032 209,143,922 9.18E-04 2.05E-03 0.52 rs924569 209,146,241 2.05E-05 2.90E-05 - 1 rs1832544 rs1832544 rs1416681 216,190,953 1.70E-04 9.42E-05 0.97 rs1567445 216,193,349 3.98E-04 2.67E-04 0.95 rs4846249 216,194,417 3.98E-04 2.67E-04 0.95 rs1832544 216,200,160 5.33E-05 3.08E-05 - rs17047145 216,225,379 8.66E-04 4.61E-04 0.81 rs11803520 216,225,993 1.28E-03 7.06E-04 0.82 1 rs12028581 rs12028581 rs2587530 232,968,563 7.34E-04 6.53E-04 0.74 rs12028581 232,974,793 2.93E-04 3.05E-04 - 2 rs4971648 rs4971648 rs970896 50,162,489 1.06E-03 6.83E-04 0.80 rs12472743 50,166,109 2.14E-04 9.47E-05 0.97 rs10490241 50,185,814 8.83E-04 3.88E-04 0.73 rs9309176 50,185,904 5.75E-04 2.56E-04 0.42 rs4971648 50,193,020 9.67E-05 4.42E-05 - rs1517827 50,231,092 3.15E-04 1.28E-04 0.91 rs1452769 50,249,639 4.95E-04 3.87E-04 0.74 rs1377238 50,252,406 1.39E-03 9.36E-04 0.68 rs17040117 50,263,307 4.81E-04 3.67E-04 0.65 rs17040210 50,288,245 8.32E-04 5.97E-04 0.65 2 rs10181805 rs10181805 rs10181805 148,053,633 8.50E-05 7.68E-05 - 2 rs1405213 rs1405213 rs848244 150,348,500 9.36E-04 3.34E-04 0.87 rs10175623 150,368,637 4.40E-04 1.56E-04 0.98

SUPPLEMENTARY DATA


rs4667395 150,372,070 1.16E-03 4.24E-04 0.87 rs1405214 150,379,011 8.70E-05 3.63E-05 1.00 rs1405213 150,379,215 7.17E-05 2.93E-05 - rs7420486 150,384,182 1.18E-04 4.03E-05 0.85 rs11889862 150,405,394 7.58E-04 4.24E-04 0.73 2 rs7597915 rs7597915 rs16830435 152,463,844 3.87E-04 3.49E-04 0.49 rs7597915 152,516,714 9.30E-05 3.74E-05 - 2 rs236833 rs236833 rs236833 205,517,999 2.17E-04 5.99E-04 - rs236830 205,526,456 3.76E-04 8.98E-04 0.65 rs236829 205,527,131 2.38E-04 6.74E-04 0.67 2 rs207851 rs207851 rs7597209 216,813,952 3.69E-03 9.78E-04 0.81 rs207851 216,821,680 9.19E-04 1.87E-04 - 3 rs2574720 rs2574720 rs2596811 11,604,413 1.08E-03 4.39E-04 0.65 rs2574704 11,630,381 1.52E-03 5.62E-04 0.69 rs2574720 11,635,412 1.03E-04 4.07E-05 - rs3856802 11,642,714 1.05E-03 4.37E-04 0.68 3 rs2070478 rs2070478 rs2070478 37,501,989 1.86E-04 1.77E-04 - 3 rs2322272 rs2322272 rs2322272 72,259,305 7.04E-05 9.13E-05 - 3 rs867829 rs867829 rs867829 148,380,315 1.63E-04 9.23E-05 - 3 rs4364195,

rs4894535 rs4364195 rs6803181 173,414,950 8.88E-04 9.75E-04 0.62

rs6445047 173,419,708 2.87E-05 9.51E-05 0.98 rs7428410 173,426,167 2.27E-05 7.61E-05 0.98 rs13073573 173,428,043 2.53E-05 8.22E-05 0.98 rs4364195 173,433,854 1.47E-05 5.12E-05 - rs1039027 173,447,803 3.10E-04 8.63E-04 0.87 rs12637941 173,455,357 1.50E-04 1.87E-04 0.59 rs13094089 173,456,295 2.43E-04 7.22E-04 0.85 rs4894535 173,478,299 3.65E-05 4.17E-05 0.38 3 rs6445073 rs6445073 rs6445073 173,859,301 7.56E-04 2.70E-03 - 4 rs1316686 rs1316686 rs1316686 14,462,589 5.71E-05 9.55E-05 - 4 rs13120537 rs13120537 rs17457078 35,830,027 3.18E-04 2.11E-04 0.95 rs13109154 35,833,305 3.97E-04 2.67E-04 0.95 rs13120537 35,869,883 1.34E-04 9.92E-05 - 4 rs17598636,

rs17640893, rs7658410

rs17598636 rs17640893 46,534,890 2.09E-06 3.51E-06 1.00 rs17598636 46,547,971 1.71E-06 2.86E-06 - rs7658410 46,666,081 9.79E-05 1.51E-04 0.80 4 rs12643813 rs12643813 rs12643813 162,504,076 1.67E-04 1.11E-04 - 4 rs1565469 rs1565469 rs7655498 172,778,374 1.31E-04 1.52E-04 0.99 rs1565469 172,789,534 1.25E-04 1.60E-04 - 5 rs7722385 rs7722385 rs7722385 16,714,282 1.71E-04 5.18E-04 - 5 rs10052705 rs10052705 rs6892045 107,109,323 6.16E-04 5.00E-04 0.50 rs10052705 107,121,047 5.61E-04 2.09E-04 - rs17160517 107,121,389 5.35E-04 2.05E-04 1.00 rs13358604 107,138,345 7.91E-04 3.47E-04 0.97 5 rs3853477 rs3853477 rs3853477 141,813,688 1.24E-04 1.42E-04 - rs4912639 141,822,109 3.44E-04 3.99E-04 0.86

SUPPLEMENTARY DATA


rs4912854 141,822,156 4.64E-04 5.51E-04 0.86 6 rs2206734 rs7758851 20,650,200 1.59E-03 6.51E-04 0.14 rs7756211 20,661,764 1.91E-03 8.22E-04 0.15 rs9350268 20,727,982 1.03E-03 6.63E-04 0.33 rs2206579 20,733,613 2.81E-04 1.50E-04 0.22 rs2328529 20,739,932 1.89E-08 1.25E-08 0.63 rs9348440 20,749,315 1.94E-09 7.29E-10 0.78 rs2328531 20,751,731 6.27E-08 1.89E-08 0.45 rs9460540 20,756,741 2.08E-08 5.42E-09 0.44 rs9295475 20,760,744 1.72E-09 7.23E-10 0.78 rs4712523 20,765,543 8.20E-10 2.43E-10 0.77 rs6906327 20,767,438 5.09E-10 1.93E-10 0.79 rs7754840 20,769,229 6.78E-10 2.55E-10 0.80 rs979614 20,770,102 4.13E-08 1.14E-08 0.45 rs9356743 20,775,667 4.08E-05 3.82E-05 0.36 rs9350270 20,775,778 6.96E-06 7.12E-06 0.49 rs1569699 20,787,289 1.51E-07 1.20E-07 0.63 rs7756992 20,787,688 2.57E-07 1.92E-07 0.64 rs2206734 20,802,863 7.17E-11 2.33E-11 - rs6931514 20,811,931 5.60E-07 4.39E-07 0.64 rs10946403 20,825,383 1.36E-07 9.45E-08 0.64 rs12111351 20,832,537 2.39E-07 1.06E-07 0.68 rs6928012 20,836,492 1.48E-04 9.67E-05 0.33 7 rs10261234,

rs12536822 rs10261234 rs10261234 12,063,192 6.55E-05 5.21E-05 -

rs10251790 12,064,226 5.19E-04 3.10E-04 0.27 rs7782424 12,093,467 7.02E-04 5.60E-04 0.30 rs10950384 12,120,607 2.21E-03 6.27E-04 0.20 rs2192740 12,131,920 1.31E-04 8.82E-05 0.25 rs2058641 12,140,428 8.96E-04 8.86E-04 0.21 rs12536822 12,162,916 2.06E-04 1.23E-04 0.18 7 rs1117750 rs1117750 rs1117750 14,854,943 1.16E-03 2.05E-03 - 7 rs17544225 rs17544225 rs17544225 50,655,548 1.72E-04 1.11E-04 - rs10486757 50,661,352 2.09E-04 1.25E-04 0.96 7 rs1442244 rs1442244 rs1442244 52,609,839 2.84E-04 4.16E-04 - rs9642489 52,618,131 5.56E-04 7.96E-04 0.99 rs17135206 52,623,046 7.56E-04 1.04E-03 0.72 rs2877031 52,624,891 7.56E-04 1.04E-03 0.71 7 rs10277213 rs10277213 rs10277213 89,914,649 2.25E-04 1.17E-04 - rs11563427 89,920,196 4.00E-04 2.46E-04 0.94 7 rs13236754 rs13236754 rs9640538 148,396,620 1.41E-03 8.63E-04 0.91 rs7778766 148,437,662 7.81E-04 4.14E-04 0.97 rs13236754 148,476,706 2.94E-04 1.60E-04 - rs3735311 148,508,670 2.66E-04 1.44E-04 0.99 8 rs4732948 rs4732948 rs4732948 29,359,445 1.04E-04 9.08E-05 - 8 rs6983230,

rs7833031 rs6983230 rs6472207 66,636,751 4.11E-04 4.86E-04 0.78

rs4737740 66,637,421 1.61E-04 1.80E-04 0.94

SUPPLEMENTARY DATA


rs4236943 66,660,114 9.42E-05 1.03E-04 1.00 rs6983230 66,704,190 9.74E-05 1.06E-04 - rs10808746 66,807,267 2.13E-04 1.73E-04 0.88 rs7833031 66,808,103 1.79E-04 1.57E-04 0.87 8 rs10808374 rs10808374 rs10808374 102,735,308 6.08E-05 6.87E-05 - 8 rs13266634 rs13266634 rs2466300 118,252,105 1.65E-03 6.92E-04 0.17 rs2464592 118,252,732 1.66E-03 7.39E-04 0.16 rs2466297 118,253,073 1.02E-03 4.14E-04 0.16 rs2466296 118,253,308 1.22E-03 4.86E-04 0.16 rs13266634 118,253,964 9.08E-04 4.42E-04 - rs2466291 118,259,574 1.12E-03 5.38E-04 0.16 rs2466318 118,286,488 1.29E-03 6.25E-04 0.16 8 rs7386204 rs7386204 rs7386204 143,180,422 1.07E-05 5.42E-05 - rs7819659 143,182,478 2.58E-05 9.55E-05 0.82 rs902829 143,187,910 1.80E-04 6.36E-04 0.80 9 rs600951 rs600951 rs478882 195,964 7.22E-04 1.07E-03 0.63 rs2479319 209,528 2.31E-04 2.50E-04 0.96 rs604470 213,979 8.70E-05 8.67E-05 0.99 rs600951 214,742 5.72E-05 6.04E-05 - rs589627 214,976 2.34E-04 2.66E-04 0.96 rs492887 247,973 1.11E-03 8.69E-04 0.67 rs492934 247,985 1.05E-03 8.04E-04 0.67 9 rs10814916 rs10814916 rs10814916 4,283,150 3.42E-03 1.01E-03 - 9 rs2383208 rs2383208 rs10965243 22,120,065 1.50E-08 4.56E-09 0.79 rs2383208 22,122,076 1.46E-08 4.00E-09 - 10 rs668498 rs668498 rs686854 5,958,650 2.34E-04 1.51E-04 0.94 rs2320 5,970,518 1.25E-04 7.44E-05 0.95 rs591878 5,975,443 1.27E-04 7.66E-05 0.96 rs636578 5,978,550 1.42E-04 8.13E-05 0.96 rs649537 5,985,678 7.06E-05 4.24E-05 0.98 rs595923 5,991,031 6.60E-05 4.08E-05 0.99 rs668498 5,998,078 4.46E-05 2.60E-05 - rs610093 6,002,641 4.60E-05 3.03E-05 0.99 rs633797 6,012,371 9.97E-05 6.40E-05 0.99 rs633930 6,017,941 6.35E-05 3.95E-05 0.99 10 rs11257655 rs11257655 rs10508438 12,284,085 3.49E-04 2.51E-04 0.56 rs12221133 12,293,603 3.91E-05 4.77E-05 0.82 rs4478891 12,307,660 6.21E-04 1.00E-03 0.74 rs10906104 12,320,302 4.87E-04 5.82E-04 0.49 rs7916879 12,340,796 1.94E-04 3.89E-04 0.86 rs10906111 12,342,363 4.05E-05 7.76E-05 0.94 rs11257655 12,347,900 1.05E-05 2.10E-05 - rs10906115 12,355,003 9.86E-05 1.27E-04 0.76 10 rs5015480 rs5015480 rs5015480 94,455,539 5.14E-04 4.45E-04 - 10 rs11188904 rs11188904 rs11188904 98,498,272 1.38E-04 1.82E-04 - rs7919352 98,503,804 5.00E-04 5.04E-04 0.23

SUPPLEMENTARY DATA


10 rs10886471 rs10886471 rs10886471 121,139,393 1.48E-05 2.86E-05 - 10 rs718948 rs718948 rs718948 126,729,328 2.72E-04 2.73E-04 - 11 rs11827207 rs11827207 rs11827207 2,651,287 5.80E-04 6.58E-04 - 11 rs2299620 rs163171 2,777,641 8.61E-04 8.29E-04 0.42 rs2237888 2,789,481 7.23E-04 5.34E-04 0.43 rs2237892 2,796,327 1.39E-07 5.61E-08 0.73 rs163182 2,800,792 4.83E-07 1.07E-07 0.15 rs163184 2,803,645 1.86E-09 1.04E-09 0.25 rs234853 2,807,404 1.28E-08 7.05E-09 0.61 rs2299620 2,814,871 4.24E-10 1.12E-10 - rs2237896 2,815,016 1.04E-09 1.74E-10 0.93 11 rs3781683 rs3781683 rs12421551 76,490,451 1.15E-03 9.89E-04 0.74 rs3781683 76,501,726 5.67E-04 7.87E-04 - 11 rs495966 rs495966 rs1343893 79,186,389 1.88E-04 2.47E-04 0.63 rs4945375 79,194,259 6.69E-04 1.18E-03 0.63 rs10793395 79,195,511 2.88E-05 4.53E-05 0.96 rs7934283 79,202,431 6.63E-04 1.31E-03 0.56 rs495966 79,204,119 2.71E-05 4.31E-05 - 11 rs1472401 rs1472401 rs1472401 82,100,594 3.51E-04 2.54E-04 - 13 rs4559795 rs4559795 rs4559795 39,014,573 2.18E-04 3.84E-04 - rs7335390 39,015,228 2.18E-04 3.84E-04 1.00 rs2324335 39,015,821 2.23E-04 3.96E-04 1.00 13 rs4620862 rs4620862 rs4620862 45,191,662 1.21E-04 6.20E-05 - rs9595373 45,195,872 9.24E-04 4.38E-04 0.71 13 rs7336343 rs7336343 rs7336343 71,336,188 6.15E-04 3.63E-04 - 14 rs12589387 rs12589387 rs12589387 85,020,219 1.70E-04 3.37E-04 - 14 rs4391997 rs4391997 rs4391997 89,899,082 2.23E-04 7.44E-05 - rs11626241 89,906,118 2.67E-03 8.84E-04 0.93 14 rs1768111 rs1768111 rs1768111 94,431,905 2.01E-05 1.97E-05 - 14 rs234146 rs234146 rs234146 97,224,265 9.56E-05 1.48E-04 - 15 rs2873027 rs2873027 rs17560758 24,387,495 8.46E-04 7.35E-04 0.68 rs2873027 24,418,502 4.92E-04 4.73E-04 - rs2315906 24,418,666 5.77E-04 5.26E-04 0.99 15 rs8030388 rs8030388 rs8030388 36,457,453 2.36E-04 6.11E-04 - rs4533240 36,475,160 3.94E-04 9.32E-04 0.97 15 rs7403531 rs7403531 rs11073332 36,604,906 5.01E-04 4.77E-04 0.85 rs7403531 36,610,197 1.55E-04 1.17E-04 - 15 rs7172432 rs7172432 rs7172432 60,183,681 8.08E-04 2.85E-04 - 15 rs10519219 rs10519219 rs10519219 76,977,187 4.99E-04 2.42E-04 - 15 rs3862435,

rs4566137 rs3862435 rs3862435 88,883,536 1.00E-04 1.30E-04 -

rs13313427 88,891,772 1.66E-04 3.53E-04 0.47 rs4566137 88,898,968 1.08E-04 2.11E-04 0.51 rs10852136 88,940,802 5.30E-04 9.85E-04 0.44 16 rs1346491,

rs7184792 rs1346491 rs1346491 12,708,927 3.97E-05 2.66E-05 -

rs882908 12,724,741 1.30E-04 6.64E-05 0.83

SUPPLEMENTARY DATA


rs7184792 12,755,890 7.34E-05 2.96E-05 0.59 16 rs7199979,

rs4785345 rs7199979 rs4785345 48,365,223 1.87E-05 6.82E-06 0.86

rs4785346 48,366,033 1.72E-05 6.32E-06 0.86 rs7199979 48,371,167 3.50E-06 1.10E-06 - 16 rs17258832 rs17258832 rs17258832 50,345,911 1.86E-04 1.31E-04 - 16 rs2221746 rs2221746 rs11076322 58,099,538 1.39E-04 3.25E-04 0.21 rs2221746 58,126,224 1.20E-05 1.83E-05 - rs12446321 58,131,998 1.22E-04 3.71E-04 0.23 16 rs6564447 rs6564447 rs1389522 76,111,968 3.15E-04 5.08E-04 0.71 rs6564447 76,123,560 1.03E-04 1.18E-04 - rs17622313 76,127,306 5.27E-04 8.06E-04 0.70 rs373509 76,159,940 2.33E-04 2.00E-04 0.80 rs1110689 76,177,034 8.62E-04 6.14E-04 0.70 17 rs11651010 rs11651010 rs8081897 11,565,234 1.01E-03 8.41E-04 0.81 rs11651010 11,585,979 2.92E-04 3.10E-04 - 17 rs4430796 rs4430796 rs757210 33,170,628 1.63E-04 6.69E-05 0.73 rs4430796 33,172,153 4.83E-06 1.26E-06 - rs4239217 33,173,100 2.35E-06 8.86E-07 0.96 rs7501939 33,175,269 2.08E-07 8.27E-08 0.85 rs3760511 33,180,426 2.15E-07 2.40E-07 0.46 17 rs4795223 rs4795223 rs4795223 33,196,340 6.63E-06 6.82E-06 - rs6607292 33,198,195 2.63E-04 2.55E-04 0.74 rs4795224 33,203,555 1.12E-05 1.16E-05 0.96 18 rs4798615,

rs1106701 rs4798615 rs1106701 8,179,364 1.21E-04 5.61E-05 0.80

rs11875152 8,183,657 4.39E-05 2.41E-05 1.00 rs4798615 8,184,433 4.24E-05 2.33E-05 - rs976168 8,210,827 1.48E-03 4.22E-04 0.34 19 rs12609246 rs12609246 rs12609246 43,601,479 3.63E-04 2.82E-04 - rs892055 43,604,604 7.81E-04 1.01E-03 0.66 19 rs4802887,

rs1078734 rs4802887 rs12976749 43,811,334 7.25E-04 3.51E-04 0.20

rs1966961 43,952,310 2.93E-04 9.56E-05 0.48 rs4802887 43,988,159 2.07E-06 9.82E-07 - rs1078734 44,000,714 2.80E-05 2.03E-05 0.68 rs7248208 44,009,846 1.31E-03 9.36E-04 0.52 19 rs2569491 rs2569491 rs9304708 56,275,748 1.18E-03 9.42E-04 0.95 rs17658926 56,276,222 4.92E-04 3.90E-04 0.85 rs10500304 56,276,410 6.78E-04 6.11E-04 0.97 rs2569491 56,276,728 2.57E-04 2.65E-04 - 20 rs2424155 rs2424155 rs6111901 18,208,846 9.23E-04 1.23E-03 0.58 rs3829702 18,234,080 8.86E-04 1.64E-03 0.28 rs2424155 18,239,064 1.74E-04 2.37E-04 - rs6045357 18,280,881 1.99E-04 3.41E-04 0.75 20 rs11696113 rs11696113 rs11696113 31,076,305 3.40E-04 4.16E-04 - 21 rs1489734 rs1489734 rs1489734 19,793,599 8.79E-05 4.93E-05 - 22 rs196094 rs196094 rs196094 37,179,625 8.32E-05 2.16E-04 - X rs1026162 rs1026162 rs1026162 6,641,810 1.53E-06 3.16E-06 -

SUPPLEMENTARY DATA


X rs5945326, rs12010175

rs5945326 rs4144871 152,490,925 1.06E-06 2.80E-07 0.22 rs12010175 152,515,832 2.03E-07 4.47E-08 0.38 rs869131 152,522,337 2.41E-05 2.00E-05 0.16 rs4328010 152,531,191 6.44E-08 4.60E-08 0.91 rs5945326 152,553,116 7.02E-09 4.24E-09 - rs5945157 152,555,094 8.30E-08 4.83E-08 0.80 rs3761534 152,560,745 2.34E-07 1.22E-07 0.74 Only the genotyped SNPs associated with T2D at P < 10-3 are shown. The 96 replication SNPs are highlighted in grey. * P values from pooled association analyses in stage 1 before and after adjusting for BMI. † r2 between SNPs and the index SNP of the genomic region.

SUPPLEMENTARY DATA


Supplementary Table 5. Associations with T2D for the 96 SNPs in stage 2

SNP CHR Nearest Gene Alleles (R/A)

RAF (cases)

RAF (controls)

Stage 1 Stage 2 Stage 1+2

N (cases/controls)

P N (cases/controls)

P * Effect direction†

OR [95% CI] P * P hetero

rs10915140 1 MATN1 C/T 0.291 0.286 1873/1839 1.62E-04 5962/6497 8.08E-01 ++- 1.04 [0.99-1.10] 1.17E-01 4.37E-03

rs4949302 1 LAPTM5 A/G 0.714 0.697 1873/1839 8.25E-05 5970/6505 5.64E-02 +-+ 1.10 [1.04-1.15] 4.15E-04 1.93E-02

rs1134767 1 INADL G/A 0.537 0.522 1870/1835 4.13E-05 5966/6500 4.25E-01 ++- 1.06 [1.02-1.11] 8.47E-03 7.88E-04

rs1984285 1 KCNN3 T/G 0.660 0.643 1873/1839 8.03E-04 5960/6485 2.24E-01 +++ 1.07 [1.02-1.12] 8.10E-03 1.27E-01

rs4656256 1 NCSTN G/A 0.372 0.359 1873/1839 1.86E-04 5966/6500 4.02E-01 ++- 1.06 [1.01-1.12] 1.24E-02 1.81E-02

rs4656902 1 NHLH1 G/T 0.128 0.123 1873/1839 1.44E-04 5973/6501 9.63E-01 -++ 1.07 [1.00-1.14] 7.95E-02 4.59E-03

rs12563833 1 TNN A/G 0.435 0.432 1872/1838 8.25E-05 5969/6500 5.72E-01 -+- 1.03 [0.99-1.08] 1.74E-01 2.50E-03

rs924569 1 KCNH1 T/C 0.783 0.774 1873/1839 2.05E-05 5972/6509 8.94E-01 ++- 1.06 [1.01-1.12] 3.37E-02 8.41E-04

rs1832544 1 SPATA17 A/G 0.796 0.786 1873/1839 5.33E-05 5959/6495 7.47E-01 -++ 1.06 [1.01-1.13] 2.86E-02 1.61E-03

rs12028581 1 IRF2BP2 C/T 0.852 0.843 1873/1839 2.93E-04 5967/6494 3.62E-01 +-+ 1.09 [1.02-1.16] 1.21E-02 1.55E-02

rs4971648 2 NRXN1 A/G 0.362 0.355 1873/1839 9.67E-05 5965/6501 2.37E-01 --+ 1.02 [0.97-1.07] 4.23E-01 1.93E-04

rs10181805 2 ACVR2A A/C 0.186 0.183 1873/1839 8.50E-05 5976/6505 5.63E-02 --- 1.01 [0.95-1.07] 8.61E-01 1.58E-04

rs1405213 2 MMADHC A/G 0.631 0.623 1873/1839 7.17E-05 5961/6510 9.63E-01 +-- 1.05 [1.00-1.10] 6.71E-02 1.22E-03

rs7597915 2 CACNB4 G/A 0.160 0.152 1871/1838 9.30E-05 5975/6496 5.25E-01 ++- 1.08 [1.02-1.15] 1.64E-02 1.84E-02

rs236833 2 PARD3B A/C 0.267 0.262 1872/1839 2.17E-04 5963/6487 1.76E-01 --+ 1.02 [0.96-1.07] 5.80E-01 5.34E-04

rs207851 2 MARCH4 C/T 0.520 0.501 1872/1839 9.19E-04 5957/6500 6.38E-02 ++- 1.08 [1.03-1.13] 1.42E-03 9.99E-02

rs2574720 3 VGLL4 T/G 0.497 0.481 1873/1839 1.03E-04 5955/6505 2.39E-01 +-+ 1.07 [1.02-1.12] 4.20E-03 6.33E-03

rs2070478 3 ITGA9 C/T 0.722 0.710 1873/1838 1.86E-04 5967/6508 2.16E-01 +++ 1.08 [1.02-1.13] 4.40E-03 4.77E-02

rs2322272 3 RYBP T/C 0.140 0.127 1873/1839 7.04E-05 5980/6506 5.52E-02 ++- 1.13 [1.06-1.21] 3.78E-04 3.77E-02

rs867829 3 ZIC4 C/T 0.760 0.757 1873/1839 1.63E-04 5974/6510 1.50E-01 +-- 1.01 [0.96-1.07] 6.07E-01 6.46E-04

rs4364195 3 FNDC3B G/A 0.450 0.446 1865/1838 1.47E-05 5961/6488 1.89E-01 --+ 1.02 [0.98-1.07] 3.73E-01 1.30E-05

rs4894535 3 FNDC3B T/C 0.355 0.348 1872/1839 3.65E-05 5949/6494 5.04E-01 --+ 1.03 [0.99-1.09] 1.74E-01 1.03E-03

rs6445073 3 NCEH1 A/G 0.319 0.296 1873/1839 7.56E-04 2844/3261 1.33E-01 ?+? 1.11 [1.04-1.18] 1.26E-03 8.33E-02

rs1316686 4 BC113726 A/G 0.686 0.667 1872/1839 5.71E-05 5980/6509 1.28E-01 +++ 1.08 [1.03-1.14] 1.23E-03 2.01E-02

rs13120537 4 ARAP2 C/T 0.091 0.091 1873/1839 1.34E-04 5972/6503 9.05E-02 +-- 1.02 [0.94-1.10] 7.53E-01 1.65E-04

SUPPLEMENTARY DATA


rs17640893 4 COX7B2 G/A 0.913 0.904 1858/1828 2.09E-06 4673/5029 8.64E-01 +-? 1.12 [1.03-1.23] 9.44E-03 3.08E-04

rs17598636 4 COX7B2 T/C 0.913 0.904 1873/1838 1.71E-06 4677/5024 9.68E-01 +-? 1.12 [1.02-1.22] 1.46E-02 1.51E-04

rs7658410 4 GABRA4 C/T 0.913 0.905 1872/1836 9.79E-05 5976/6508 4.65E-01 +-+ 1.11 [1.02-1.20] 1.33E-02 1.17E-02

rs12643813 4 FSTL5 G/A 0.345 0.331 1873/1839 1.67E-04 5940/6445 2.77E-01 -+- 1.07 [1.02-1.12] 6.22E-03 1.14E-02

rs1565469 4 GALNTL6 A/G 0.424 0.419 1873/1839 1.25E-04 5968/6500 4.37E-01 --+ 1.03 [0.98-1.08] 2.59E-01 2.24E-03

rs7722385 5 MYO10 C/T 0.829 0.823 1873/1839 1.71E-04 5966/6510 4.81E-01 -+- 1.04 [0.97-1.10] 2.49E-01 1.43E-03

rs10052705 5 EFNA5 A/G 0.715 0.710 1873/1839 5.61E-04 5938/6463 5.62E-01 --+ 1.03 [0.98-1.08] 2.63E-01 3.75E-03

rs3853477 5 SPRY4 T/C 0.227 0.217 1873/1838 1.24E-04 5964/6515 5.74E-01 -+- 1.07 [1.01-1.13] 2.13E-02 4.63E-03

rs10261234 7 TMEM106B A/G 0.760 0.744 1873/1839 6.55E-05 5931/6504 7.92E-03 +++ 1.12 [1.06-1.18] 2.50E-05 1.64E-01

rs12536822 7 TMEM106B A/G 0.764 0.754 1873/1839 2.06E-04 5945/6495 4.20E-01 +++ 1.07 [1.01-1.13] 1.39E-02 4.01E-02

rs1117750 7 DGKB C/T 0.713 0.707 1873/1839 1.16E-03 5956/6503 3.83E-01 -+- 1.02 [0.97-1.07] 4.44E-01 2.98E-03

rs17544225 7 GRB10 C/T 0.110 0.101 1873/1839 1.72E-04 5978/6504 2.88E-01 ++- 1.11 [1.03-1.19] 6.84E-03 6.46E-03

rs1442244 7 POM121L12 A/G 0.618 0.594 1873/1839 2.84E-04 5972/6502 4.23E-02 +++ 1.09 [1.04-1.14] 4.77E-04 1.44E-01

rs10277213 7 CLDN12 A/G 0.901 0.893 1873/1839 2.25E-04 5954/6503 8.92E-01 -++ 1.07 [0.99-1.15] 1.05E-01 1.16E-02

rs13236754 7 ZNF398 G/A 0.107 0.091 1873/1839 2.94E-04 3032/3138 1.56E-02 +?+ 1.22 [1.11-1.34] 4.20E-05 2.94E-01

rs4732948 8 DUSP4 G/A 0.838 0.823 1873/1839 1.04E-04 5844/6444 2.08E-02 -++ 1.13 [1.06-1.20] 1.11E-04 3.13E-02

rs6983230 8 ARMC1 G/A 0.616 0.607 1873/1839 9.74E-05 5971/6511 6.38E-01 -+- 1.04 [0.99-1.08] 1.54E-01 1.21E-03

rs7833031 8 PDE7A A/G 0.597 0.588 1873/1839 1.79E-04 5958/6497 9.74E-01 -+- 1.04 [1.00-1.09] 7.26E-02 3.57E-03

rs10808374 8 GRHL2 T/G 0.345 0.327 1872/1839 6.08E-05 5978/6511 6.32E-02 +++ 1.09 [1.04-1.15] 4.30E-04 6.21E-02

rs13266634 8 SLC30A8 C/T 0.609 0.570 1871/1837 9.08E-04 NA NA ??? NA [NA-NA] NA NA

rs7386204 8 TSNARE1 A/G 0.664 0.649 1873/1839 1.07E-05 5970/6498 4.34E-01 -++ 1.07 [1.02-1.13] 5.73E-03 2.68E-03

rs600951 9 DOCK8 C/T 0.727 0.717 1871/1839 5.72E-05 5943/6498 7.54E-01 -++ 1.05 [0.99-1.10] 1.05E-01 1.47E-03

rs10814916 9 GLIS3 C/A 0.467 0.439 1873/1839 3.42E-03 5937/6464 3.45E-05 +++ 1.13 [1.08-1.18] 5.29E-07 6.56E-01

rs2383208 9 CDKN2B A/G 0.610 0.558 1872/1838 1.46E-08 5948/6486 5.28E-11 +++ 1.22 [1.17-1.28] 3.38E-17 1.95E-01

rs668498 10 FBXO18 T/C 0.305 0.292 1873/1839 4.46E-05 5925/6473 2.69E-01 ++- 1.08 [1.02-1.13] 3.75E-03 5.72E-03

rs11257655 10 CDC123 T/C 0.596 0.564 1873/1839 1.05E-05 5960/6489 2.22E-05 +++ 1.15 [1.10-1.20] 6.56E-09 3.18E-01

rs5015480 10 HHEX C/T 0.199 0.179 1872/1839 5.14E-04 5949/6478 3.17E-04 +++ 1.15 [1.09-1.22] 1.62E-06 5.57E-01

rs11188904 10 PIK3AP1 A/G 0.519 0.499 1865/1834 1.38E-04 5954/6493 4.30E-02 +++ 1.09 [1.04-1.14] 3.53E-04 1.03E-01

rs10886471 10 GRK5 C/T 0.802 0.778 1873/1839 1.48E-05 5957/6510 7.71E-04 +++ 1.16 [1.09-1.22] 5.92E-07 1.90E-01

rs718948 10 CTBP2 T/C 0.768 0.767 1873/1839 2.72E-04 5967/6508 7.42E-02 --- 1.01 [0.95-1.06] 8.82E-01 6.15E-04

SUPPLEMENTARY DATA


rs11827207 11 KCNQ1 G/A 0.905 0.891 1871/1839 5.80E-04 5962/6503 2.62E-02 +++ 1.15 [1.07-1.24] 3.52E-04 1.89E-01

rs3781683 11 CAPN5 T/C 0.083 0.080 1873/1839 5.67E-04 5972/6498 6.08E-01 --+ 1.05 [0.97-1.14] 2.40E-01 8.39E-03

rs495966 11 ODZ4 C/T 0.451 0.441 1873/1839 2.71E-05 5948/6468 6.07E-01 -+- 1.04 [0.99-1.09] 1.25E-01 1.07E-03

rs1472401 11 FAM181B T/C 0.871 0.860 1872/1839 3.51E-04 5973/6500 2.97E-01 -++ 1.10 [1.02-1.17] 9.31E-03 6.60E-02

rs4559795 13 LHFP G/T 0.919 0.911 1873/1839 2.18E-04 5973/6510 5.35E-01 +-+ 1.10 [1.02-1.20] 2.22E-02 2.19E-02

rs4620862 13 SPERT T/C 0.205 0.194 1873/1839 1.21E-04 5981/6504 5.17E-01 +++ 1.07 [1.01-1.14] 1.72E-02 2.33E-02

rs7336343 13 DACH1 T/C 0.803 0.793 1871/1839 6.15E-04 5937/6473 6.57E-01 -+- 1.06 [1.00-1.12] 4.47E-02 3.27E-02

rs12589387 14 FLRT2 T/C 0.460 0.449 1873/1839 1.70E-04 5969/6503 7.17E-01 -++ 1.05 [1.00-1.10] 3.68E-02 1.42E-02

rs4391997 14 CALM1 A/G 0.841 0.838 1873/1839 2.23E-04 5976/6510 1.47E-02 --+ 0.99 [0.93-1.06] 6.86E-01 5.96E-05

rs1768111 14 GSC A/G 0.169 0.158 1869/1838 2.01E-05 5945/6482 5.45E-01 -++ 1.08 [1.02-1.15] 1.10E-02 5.05E-03

rs234146 14 AL163872.1 T/C 0.120 0.113 1873/1839 9.56E-05 5982/6513 9.10E-01 -+- 1.08 [1.00-1.16] 5.25E-02 7.04E-03

rs2873027 15 GABRB3 G/A 0.814 0.807 1873/1839 4.92E-04 5948/6497 8.15E-01 +-+ 1.04 [0.99-1.11] 1.50E-01 1.10E-02

rs8030388 15 SPRED1 C/T 0.191 0.177 1873/1839 2.36E-04 5967/6503 1.78E-01 +++ 1.09 [1.03-1.16] 3.55E-03 3.78E-02

rs7403531 15 RASGRP1 T/C 0.374 0.346 1872/1839 1.55E-04 5977/6498 2.12E-05 +++ 1.15 [1.09-1.20] 3.42E-08 4.62E-01

rs7172432 15 C2CD4A A/G 0.621 0.597 1873/1839 8.08E-04 5959/6506 3.10E-02 +++ 1.09 [1.04-1.14] 5.15E-04 2.64E-01

rs10519219 15 MORF4L1 T/C 0.697 0.682 1873/1839 4.99E-04 5948/6479 2.37E-01 +++ 1.07 [1.02-1.12] 7.34E-03 6.97E-02

rs3862435 15 CRTC3 A/G 0.190 0.183 1873/1839 1.00E-04 5964/6504 3.10E-01 --- 1.03 [0.97-1.09] 3.45E-01 1.30E-03

rs4566137 15 CRTC3 A/G 0.242 0.225 1873/1839 1.08E-04 3094/3170 8.72E-01 -?+ 1.09 [1.02-1.16] 1.41E-02 9.30E-03

rs1346491 16 CPPED1 C/T 0.724 0.723 1873/1839 3.97E-05 5977/6515 6.67E-02 --- 1.01 [0.96-1.06] 7.45E-01 1.32E-04

rs7184792 16 CPPED1 A/G 0.629 0.624 1873/1839 7.34E-05 5942/6499 4.65E-01 +-- 1.03 [0.98-1.08] 2.19E-01 1.11E-03

rs4785345 16 ZNF423 C/T 0.779 0.770 1873/1839 1.87E-05 5951/6488 3.53E-01 +-+ 1.03 [0.98-1.09] 2.29E-01 2.08E-04

rs7199979 16 ZNF423 C/T 0.755 0.745 1872/1839 3.50E-06 5951/6490 4.94E-01 +-+ 1.04 [0.99-1.10] 1.12E-01 1.14E-04

rs17258832 16 LOC388276 A/C 0.132 0.123 1873/1839 1.86E-04 3098/3175 5.04E-01 +?- 1.07 [0.98-1.17] 8.71E-02 1.20E-03

rs2221746 16 G/A 0.676 0.661 1873/1839 1.20E-05 4516/4877 7.31E-01 -+? 1.07 [1.02-1.13] 9.75E-03 6.37E-04

rs6564447 16 ADAMTS18 G/A 0.348 0.339 1873/1839 1.03E-04 5964/6503 9.47E-01 -++ 1.05 [1.00-1.10] 7.61E-02 1.66E-03

rs11651010 17 DNAH9 C/T 0.869 0.862 1873/1839 2.92E-04 5975/6512 8.35E-01 -+- 1.07 [1.00-1.14] 5.88E-02 1.22E-03

rs4430796 17 HNF1B G/A 0.310 0.276 1869/1837 4.83E-06 5961/6499 1.67E-07 +++ 1.19 [1.13-1.25] 1.52E-11 3.00E-01

rs4795223 17 HNF1B C/T 0.387 0.368 1873/1839 6.63E-06 5958/6501 1.26E-01 +++ 1.09 [1.04-1.14] 5.31E-04 1.39E-02

rs1106701 18 PTPRM C/T 0.117 0.109 1873/1838 1.21E-04 4633/4982 9.77E-01 +-? 1.08 [1.00-1.17] 4.86E-02 2.25E-03

rs4798615 18 PTPRM G/A 0.127 0.122 1873/1839 4.24E-05 5881/6432 4.10E-01 +-- 1.04 [0.97-1.12] 2.24E-01 3.75E-04

SUPPLEMENTARY DATA


rs12609246 19 RASGRP4 G/A 0.530 0.534 1873/1839 3.63E-04 5966/6503 2.79E-02 --- 0.99 [0.95-1.04] 8.03E-01 3.96E-04

rs4802887 19 LGALS4 T/G 0.302 0.293 1873/1839 2.07E-06 5975/6502 9.54E-01 -+- 1.06 [1.01-1.12] 2.23E-02 2.73E-04

rs1078734 19 ECH1 T/C 0.277 0.266 1873/1839 2.80E-05 5967/6503 3.67E-01 -++ 1.08 [1.02-1.14] 5.67E-03 1.33E-02

rs2569491 19 KLK14 A/G 0.109 0.105 1873/1839 2.57E-04 5970/6513 3.70E-01 -+- 1.03 [0.96-1.11] 3.50E-01 3.64E-04

rs2424155 20 ZNF133 T/C 0.411 0.399 1873/1838 1.74E-04 5945/6480 5.84E-01 ++- 1.05 [1.01-1.10] 2.43E-02 5.64E-03

rs11696113 20 BPIL1 T/C 0.138 0.132 1872/1839 3.40E-04 5899/6454 7.75E-01 -+- 1.05 [0.98-1.12] 1.49E-01 1.05E-02

rs1489734 21 LOC100505973 C/T 0.434 0.425 1873/1839 8.79E-05 5947/6477 7.22E-01 -+- 1.04 [0.99-1.09] 1.23E-01 1.20E-03

rs196094 22 KCNJ4 A/G 0.803 0.796 1873/1839 8.32E-05 3031/3128 1.75E-01 -?- 1.05 [0.97-1.12] 1.92E-01 2.14E-04

rs1026162 X HDHD1 C/T 0.891 0.884 1873/1839 1.53E-06 5942/6477 7.88E-01 -+- 1.06 [1.00-1.13] 4.21E-02 9.29E-05

rs12010175 X FAM58A G/A 0.828 0.786 1873/1839 2.03E-07 3053/3148 2.49E-04 +?+ 1.21 [1.14-1.28] 1.67E-09 4.95E-02

rs5945326 X DUSP9 A/G 0.657 0.606 1862/1834 7.02E-09 5804/6346 1.15E-09 +++ 1.18 [1.13-1.23] 6.66E-16 1.01E-01

The associations of each SNP with T2D were not adjusted for BMI. P values in stage 1 were corrected for genomic control before meta-analyses. * Results of meta-analysis that combined data of stage 2 or of stage 1 and 2. The reported SNPs are highlighted in grey. RAF: Risk allele frequency, R/A: Risk allele/Alternative allele, NA: not available. †The “+” refer to the consistent association direction in samples from the GBTDS, BTDS, and HTDS studies as that in stage 1, whereas “-“ refers to the reverse association direction, and “?” refers to failure in the.quality.control.testing.

SUPPLEMENTARY DATA


Supplementary Table 6. Associations with T2D stratified by sex for the 96 SNPs in stage 1 and 2


Male Female Phetero

OR [95% CI] * P * OR [95% CI] * P * rs10915140 1 MATN1 C/T 1.03 [0.96-1.11] 4.09E-01 1.05 [0.98-1.13] 1.63E-01 0.67

rs4949302 1 LAPTM5 A/G 1.12 [1.05-1.20] 1.47E-03 1.06 [0.99-1.14] 1.13E-01 0.27

rs1134767 1 INADL G/A 1.10 [1.03-1.17] 3.32E-03 1.03 [0.96-1.10] 3.87E-01 0.16

rs1984285 1 KCNN3 T/G 1.06 [0.99-1.14] 7.06E-02 1.08 [1.01-1.16] 2.39E-02 0.72

rs4656256 1 NCSTN G/A 1.06 [0.99-1.13] 1.14E-01 1.07 [1.00-1.15] 4.45E-02 0.73

rs4656902 1 NHLH1 G/T 1.07 [0.97-1.18] 1.63E-01 1.05 [0.95-1.16] 3.47E-01 0.75

rs12563833 1 TNN A/G 1.04 [0.98-1.11] 2.19E-01 1.02 [0.96-1.09] 5.04E-01 0.70

rs924569 1 KCNH1 T/C 1.02 [0.94-1.10] 7.04E-01 1.10 [1.02-1.19] 1.52E-02 0.14

rs1832544 1 SPATA17 A/G 1.06 [0.98-1.15] 1.38E-01 1.08 [0.99-1.17] 7.79E-02 0.82

rs12028581 1 IRF2BP2 C/T 1.06 [0.97-1.16] 1.74E-01 1.11 [1.01-1.21] 2.40E-02 0.52

rs4971648 2 NRXN1 A/G 1.02 [0.95-1.08] 6.58E-01 1.02 [0.96-1.10] 5.18E-01 0.88

rs10181805 2 ACVR2A A/C 1.02 [0.94-1.11] 6.84E-01 1.00 [0.92-1.09] 9.58E-01 0.80

rs1405213 2 MMADHC A/G 1.03 [0.97-1.10] 3.42E-01 1.07 [1.00-1.14] 6.69E-02 0.52

rs7597915 2 CACNB4 G/A 1.10 [1.01-1.20] 3.48E-02 1.07 [0.97-1.17] 1.67E-01 0.62

rs236833 2 PARD3B A/C 1.07 [0.99-1.15] 8.71E-02 0.96 [0.89-1.04] 2.93E-01 0.05

rs207851 2 MARCH4 C/T 1.07 [1.01-1.15] 2.74E-02 1.08 [1.02-1.16] 1.42E-02 0.84

rs2574720 3 VGLL4 T/G 1.07 [1.00-1.14] 4.71E-02 1.08 [1.01-1.15] 2.53E-02 0.83

rs2070478 3 ITGA9 C/T 1.07 [1.00-1.15] 6.40E-02 1.08 [1.01-1.16] 3.32E-02 0.82

rs2322272 3 RYBP T/C 1.13 [1.03-1.24] 1.32E-02 1.13 [1.03-1.25] 1.30E-02 0.96

rs867829 3 ZIC4 C/T 0.99 [0.92-1.07] 8.07E-01 1.04 [0.96-1.12] 3.01E-01 0.37

rs4364195 3 FNDC3B G/A 1.01 [0.95-1.08] 6.55E-01 1.03 [0.97-1.10] 3.48E-01 0.72

rs4894535 3 FNDC3B T/C 1.00 [0.94-1.07] 8.99E-01 1.06 [0.99-1.14] 7.42E-02 0.24

rs6445073 3 NCEH1 A/G 1.11 [1.02-1.22] 2.04E-02 1.11 [1.01-1.21] 2.29E-02 0.96

rs1316686 4 CPEB2 A/G 1.06 [0.99-1.14] 9.39E-02 1.10 [1.03-1.18] 6.34E-03 0.45

rs13120537 4 ARAP2 C/T 1.04 [0.93-1.17] 4.97E-01 0.99 [0.89-1.11] 9.22E-01 0.58

rs17640893 4 COX7B2 G/A 1.15 [1.01-1.31] 3.13E-02 1.09 [0.97-1.24] 1.55E-01 0.58

rs17598636 4 COX7B2 T/C 1.14 [1.00-1.29] 4.24E-02 1.08 [0.96-1.23] 1.98E-01 0.57

rs7658410 4 GABRA4 C/T 1.10 [0.98-1.23] 9.26E-02 1.10 [0.99-1.24] 8.72E-02 0.97

rs12643813 4 FSTL5 G/A 1.06 [0.99-1.14] 9.37E-02 1.08 [1.01-1.16] 3.12E-02 0.73

rs1565469 4 GALNTL6 A/G 1.01 [0.95-1.08] 7.49E-01 1.04 [0.98-1.11] 2.22E-01 0.52

rs7722385 5 MYO10 C/T 1.05 [0.96-1.14] 2.64E-01 1.01 [0.93-1.11] 7.49E-01 0.58

rs10052705 5 EFNA5 A/G 1.04 [0.97-1.12] 2.26E-01 1.02 [0.95-1.10] 5.59E-01 0.67

rs3853477 5 SPRY4 T/C 1.06 [0.98-1.15] 1.14E-01 1.06 [0.98-1.15] 1.21E-01 1.00

rs10261234 7 TMEM106B A/G 1.13 [1.05-1.22] 1.02E-03 1.11 [1.03-1.20] 4.78E-03 0.75

rs12536822 7 TMEM106B A/G 1.07 [0.99-1.15] 8.64E-02 1.07 [0.99-1.16] 7.85E-02 0.95

rs1117750 7 DGKB C/T 1.01 [0.94-1.09] 7.61E-01 1.03 [0.96-1.11] 4.16E-01 0.71

rs17544225 7 GRB10 C/T 1.14 [1.03-1.26] 1.38E-02 1.08 [0.97-1.20] 1.78E-01 0.47

rs1442244 7 POM121L12 A/G 1.12 [1.05-1.2] 6.90E-04 1.06 [0.99-1.14] 7.31E-02 0.27

rs10277213 7 CLDN12 A/G 1.09 [0.98-1.21] 1.31E-01 1.06 [0.95-1.18] 3.20E-01 0.72

rs13236754 7 ZNF398 G/A 1.23 [1.08-1.4] 1.84E-03 1.20 [1.05-1.38] 9.09E-03 0.83

rs4732948 8 DUSP4 G/A 1.18 [1.08-1.28] 1.79E-04 1.08 [0.99-1.18] 9.44E-02 0.16

rs6983230 8 ARMC1 G/A 1.07 [1.00-1.14] 6.04E-02 1.01 [0.95-1.08] 6.93E-01 0.30

rs7833031 8 PDE7A A/G 1.07 [1.00-1.14] 5.00E-02 1.03 [0.96-1.10] 4.30E-01 0.42

SUPPLEMENTARY DATA


rs10808374 8 GRHL2 T/G 1.11 [1.03-1.18] 4.24E-03 1.08 [1.01-1.15] 3.21E-02 0.62

rs13266634 8 SLC30A8 C/T NA [NA-NA] NA NA [NA-NA] NA NA

rs7386204 8 TSNARE1 A/G 1.12 [1.04-1.19] 1.64E-03 1.03 [0.96-1.10] 4.65E-01 0.09

rs600951 9 DOCK8 C/T 1.01 [0.94-1.08] 8.07E-01 1.09 [1.01-1.17] 2.25E-02 0.14

rs10814916 9 GLIS3 C/A 1.11 [1.04-1.19] 9.58E-04 1.13 [1.06-1.21] 1.80E-04 0.71

rs2383208 9 CDKN2B A/G 1.27 [1.19-1.36] 5.89E-13 1.18 [1.10-1.26] 1.14E-06 0.12

rs668498 10 FBXO18 T/C 1.08 [1.01-1.16] 2.91E-02 1.07 [1.00-1.15] 5.14E-02 0.91

rs11257655 10 CDC123 T/C 1.19 [1.11-1.27] 3.64E-07 1.11 [1.04-1.19] 1.58E-03 0.20

rs5015480 10 HHEX C/T 1.15 [1.06-1.24] 1.04E-03 1.17 [1.08-1.27] 1.72E-04 0.72

rs11188904 10 PIK3AP1 A/G 1.06 [1.00-1.13] 6.77E-02 1.11 [1.04-1.19] 1.54E-03 0.32

rs10886471 10 GRK5 C/T 1.19 [1.10-1.29] 2.15E-05 1.11 [1.03-1.21] 8.98E-03 0.27

rs718948 10 CTBP2 T/C 0.96 [0.89-1.03] 2.39E-01 1.06 [0.98-1.14] 1.67E-01 0.07

rs11827207 11 KCNQ1 G/A 1.13 [1.01-1.25] 2.79E-02 1.17 [1.05-1.31] 3.79E-03 0.60

rs3781683 11 CAPN5 T/C 1.12 [1.00-1.26] 5.36E-02 0.98 [0.87-1.11] 7.66E-01 0.12

rs495966 11 ODZ4 C/T 1.05 [0.98-1.12] 1.73E-01 1.03 [0.96-1.10] 3.86E-01 0.74

rs1472401 11 FAM181B T/C 1.11 [1.01-1.22] 3.05E-02 1.08 [0.98-1.19] 1.12E-01 0.72

rs4559795 13 LHFP G/T 1.11 [0.99-1.25] 6.83E-02 1.09 [0.97-1.22] 1.57E-01 0.79

rs4620862 13 SPERT T/C 1.07 [0.98-1.16] 1.20E-01 1.07 [0.99-1.16] 9.17E-02 0.93

rs7336343 13 DACH1 T/C 1.09 [1.01-1.18] 3.07E-02 1.03 [0.95-1.12] 5.08E-01 0.31

rs12589387 14 FLRT2 T/C 1.05 [0.99-1.13] 1.05E-01 1.05 [0.98-1.12] 1.52E-01 0.91

rs4391997 14 CALM1 A/G 0.98 [0.90-1.07] 6.52E-01 1.00 [0.92-1.10] 9.21E-01 0.70

rs1768111 14 GSC A/G 1.14 [1.05-1.24] 2.93E-03 1.02 [0.93-1.11] 7.19E-01 0.07

rs234146 14 AL163872.1 T/C 1.08 [0.98-1.19] 1.42E-01 1.08 [0.98-1.20] 1.37E-01 0.96

rs2873027 15 GABRB3 G/A 1.05 [0.97-1.14] 2.15E-01 1.04 [0.96-1.13] 3.76E-01 0.82

rs8030388 15 SPRED1 C/T 1.16 [1.07-1.26] 4.54E-04 1.03 [0.95-1.12] 4.54E-01 0.05

rs7403531 15 RASGRP1 T/C 1.14 [1.06-1.21] 2.22E-04 1.14 [1.07-1.22] 1.61E-04 0.91

rs7172432 15 C2CD4A A/G 1.06 [0.99-1.13] 8.37E-02 1.12 [1.05-1.20] 1.02E-03 0.26

rs10519219 15 MORF4L1 T/C 1.04 [0.97-1.11] 3.11E-01 1.10 [1.03-1.18] 6.81E-03 0.22

rs3862435 15 CRTC3 A/G 1.03 [0.95-1.12] 4.21E-01 1.01 [0.93-1.10] 8.45E-01 0.67

rs4566137 15 CRTC3 A/G 1.11 [1.01-1.22] 3.36E-02 1.05 [0.95-1.16] 3.48E-01 0.42

rs1346491 16 CPPED1 C/T 1.04 [0.97-1.12] 2.74E-01 0.97 [0.90-1.05] 4.86E-01 0.21

rs7184792 16 CPPED1 A/G 1.06 [1.00-1.14] 6.45E-02 0.99 [0.93-1.06] 7.99E-01 0.14

rs4785345 16 ZNF423 C/T 1.00 [0.93-1.08] 9.48E-01 1.07 [0.99-1.15] 9.66E-02 0.26

rs7199979 16 ZNF423 C/T 1.02 [0.95-1.10] 6.35E-01 1.07 [0.99-1.15] 7.32E-02 0.35

rs17258832 16 LOC388276 A/C 1.10 [0.98-1.24] 1.20E-01 1.05 [0.92-1.19] 4.56E-01 0.61

rs2221746 16 G/A 1.04 [0.96-1.12] 3.18E-01 1.11 [1.03-1.20] 5.97E-03 0.20

rs6564447 16 ADAMTS18 G/A 1.04 [0.98-1.12] 2.04E-01 1.05 [0.98-1.12] 1.95E-01 0.97

rs11651010 17 DNAH9 C/T 1.12 [1.02-1.23] 1.89E-02 1.01 [0.92-1.11] 8.58E-01 0.12

rs4430796 17 HNF1B G/A 1.18 [1.10-1.27] 3.04E-06 1.19 [1.10-1.27] 4.12E-06 0.99

rs4795223 17 HNF1B C/T 1.06 [0.99-1.13] 8.28E-02 1.11 [1.04-1.19] 2.24E-03 0.34

rs1106701 18 PTPRM C/T 1.07 [0.95-1.20] 2.64E-01 1.10 [0.98-1.23] 1.15E-01 0.76

rs4798615 18 PTPRM G/A 1.02 [0.92-1.12] 7.33E-01 1.07 [0.97-1.18] 1.72E-01 0.47

rs12609246 19 RASGRP4 G/A 1.01 [0.94-1.07] 8.41E-01 0.98 [0.92-1.05] 5.46E-01 0.57

rs4802887 19 LGALS4 T/G 1.05 [0.98-1.13] 1.83E-01 1.08 [1.00-1.16] 4.48E-02 0.62

rs1078734 19 ECH1 T/C 1.04 [0.97-1.12] 2.44E-01 1.11 [1.03-1.20] 4.55E-03 0.23

rs2569491 19 KLK14 A/G 1.01 [0.91-1.12] 8.67E-01 1.05 [0.95-1.17] 3.44E-01 0.58

SUPPLEMENTARY DATA


rs2424155 20 ZNF133 T/C 1.08 [1.01-1.15] 2.00E-02 1.03 [0.96-1.10] 4.25E-01 0.29

rs11696113 20 BPIL1 T/C 1.04 [0.94-1.14] 4.61E-01 1.06 [0.96-1.17] 2.40E-01 0.74

rs1489734 21 LOC100505973 C/T 1.08 [1.01-1.15] 2.02E-02 0.99 [0.93-1.06] 7.54E-01 0.06

rs196094 22 KCNJ4 A/G 1.06 [0.96-1.17] 2.62E-01 1.04 [0.93-1.15] 5.06E-01 0.78

rs1026162 X HDHD1 C/T 1.13 [1.02-1.25] 1.73E-02 1.03 [0.95-1.11] 5.07E-01 0.13

rs12010175 X FAM58A G/A 1.24 [1.12-1.37] 1.83E-05 1.19 [1.10-1.28] 1.46E-05 0.48

rs5945326 X DUSP9 A/G 1.18 [1.10-1.25] 1.20E-06 1.17 [1.12-1.23] 2.47E-10 0.99

The associations of each SNP with T2D were not adjusted for BMI. *results of fixed-effect meta-analyses that combined stage 1 and 2 data. RAF: Risk allele frequency, R/A: Risk allele/Alternative allele

SUPPLEMENTARY DATA


Supplementary Table 7. Associations with T2D for 10 SNPs in stage 3


Stage 1+2 Stage 3 Stage 1+2+3

N OR [95% CI] P N OR [95% CI] P P P hetero *

rs4949302 1 LAPTM5 A/G 16,186 1.10 [1.04-1.15] 4.15E-04 21,303 1.06 [1.01-1.12] 1.09E-02 2.24E-05 0.46

rs2322272 3 RYBP T/C 16,197 1.13 [1.06-1.21] 3.78E-04 21,346 1.02 [0.96-1.08] 5.87E-01 6.07E-03 0.58

rs10261234 7 TMEM106B A/G 16,146 1.12 [1.06-1.18] 2.50E-05 21,339 0.97 [0.92-1.01] 1.46E-01 9.52E-02 0.05

rs1442244 7 POM121L12 A/G 16,185 1.09 [1.04-1.14] 4.77E-04 25,251 1.03 [1.99-1.07] 1.31E-01 7.73E-04 0.57

rs4732948 8 DUSP4 G/A 15,999 1.13 [1.06-1.20] 1.11E-04 25,298 1.02 [0.97-1.08] 3.50E-01 1.70E-03 0.18

rs10808374 8 GRHL2 T/G 16,199 1.09 [1.04-1.15] 4.30E-04 21,320 1.01 [0.96-1.05] 7.87E-01 1.30E-02 0.62

rs10814916 9 GLIS3 C/A 16,112 1.13 [1.08-1.18] 5.29E-07 21,325 1.11 [1.06-1.15] 1.98E-06 6.01E-12 0.54

rs11188904 10 PIK3AP1 A/G 16,145 1.09 [1.04-1.14] 3.53E-04 25,306 0.98 [0.94-1.02] 2.55E-01 1.80E-01 0.20

rs10886471 10 GRK5 C/T 16,178 1.16 [1.09-1.22] 5.92E-07 21,278 1.09 [1.04-1.15] 8.82E-04 7.10E-09 0.73

rs7403531 15 RASGRP1 T/C 16,185 1.15 [1.09-1.20] 3.42E-08 25,240 1.07 [1.02-1.11] 1.78E-03 3.90E-09 0.46

The associations of each SNP with T2D were not adjusted for BMI. P values in stage 1 were corrected for genomic control before meta-analyses.* P for heterogeneity of ORs across replication stages (Stage 2+3). R/A: Risk allele/Alternative allele.

SUPPLEMENTARY DATA


Supplementary Table 8. Associations with T2D for SNPs at GLIS3, GRK5, and RASGRP1 loci in each population N (cases/controls) OR [95% CI] * P * P hetero

GLIS3-rs10814916 (C/A)

Stage 1 (Shanghai & Beijing) 1,873/1,839 1.15 [1.05-1.27] 3.42E-03

Stage 2 (Guizhou) 1,789/1,684 1.12 [1.01-1.24] 2.62E-02

Stage 2 (Beijing) 2,851/3,301 1.09 [1.01-1.17] 2.76E-02

Stage 2 (Hubei) 1,297/1,479 1.17 [1.06-1.30] 2.86E-03

Stage 3 (SDIID/SDS) 3,250/3,249 1.15 [1.07-1.24] 1.85E-04

Stage 3 (AGEN-T2D) 5,910/8,922 1.09 [1.03-1.14] 1.27E-03

All replication stages (Stage 2+3) 15,097/18,635 1.11 [1.08-1.15] 2.56E-10 0.54

Chinese Hans (Stage 1+2+3) 15,086/16,206 1.11 [1.07-1.14] 1.13E-09 0.49

East Asians including Chinese Hans (Stage 1+2+3) 16,970/20,474 1.11 [1.08-1.15] 3.39E-12 0.50

Heterogeneity between Chinese Hans and other East Asians 0.34

GRK5-rs10886471 (T/C)


Stage 2 (Guizhou) 1,798/1,694 1.14 [1.00-1.29] 4.35E-02

Stage 2 (Beijing) 2,865/3,329 1.10 [1.01-1.21] 3.41E-02

Stage 2 (Hubei) 1,294/1,487 1.12 [0.98-1.29] 8.99E-02

Stage 3 (SDIID/SDS) 3,229/3,222 1.14 [1.04-1.25] 3.54E-03

Stage 3 (AGEN-T2D) 5,910/8,922 1.07 [1.00-1.14] 3.94E-02




Heterogeneity between Chinese Hans and other East Asians 0.14

Europeans (DIAGRAM+) 8,130/38,987 0.98 [0.94-1.02] 3.52E-01

Heterogeneity between East Asians and Europeans 4.42E-06

RASGRP1-rs7403531 (T/C)


Stage 2 (Guizhou) 1,799/1,692 1.18 [1.06-1.31] 2.30E-03

Stage 2 (Beijing) 2,881/3,322 1.11 [1.03-1.20] 8.80E-03

Stage 2 (Hubei) 1,297/1,484 1.10 [0.98-1.23] 9.28E-02

Stage 3 (SDIID/SDS) 3,254/3,258 1.05 [0.98-1.13] 1.86E-01

Stage 3 (AGEN-T2D) 6,952/11,865 1.07 [1.02-1.12] 4.29E-03




Heterogeneity between Chinese Han and other East Asian 0.74

Europeans (DIAGRAM+) 8,130/38,987 1.06 [1.01-1.11] 2.25E-02

East Asians + Europeans 26,185/62,447 1.09 [1.06-1.11] 3.70E-10 0.24

Heterogeneity between East Asians and Europeans 0.22

SUPPLEMENTARY DATA


Alleles are presented as minor/major allele, and alleles underlined are risk alleles for T2D. *Results of fixed-effect inverse variance weighted meta-analyses. P values in stage 1 were not corrected for genomic control. Supplementary Table 9. Associations with T2D for the two novel T2D SNPs after adjusting for BMI

SNP CHR Nearest Gene

Alleles (R/A)

Stage 1+2+3

not adjusted for BMI adjusted for BMI OR [95% CI] P OR [95% CI] P

rs10886471 10 GRK5 C/T 1.12 [1.08-1.16] 7.10E-09 1.12 [1.08-1.16] 1.73E-08

rs7403531 15 RASGRP1 T/C 1.10 [1.06-1.13] 3.90E-09 1.10 [1.07-1.14] 2.87E-09

P values in stage 1 were corrected for genomic control before meta-analysis. R/A: Risk allele/Alternative allel Supplementary Table 10. Characteristics of study population in the NHAPC and the GMOS studies

Characteristics NHAPC GMOS

Region Shanghai Beijing Shanghai

n (% male) 1,634 (43.5) 1,576 (45.2) 749 (41.3)

Age (years) 58.9 ± 6.0 58.3 ± 5.9 45.7 ± 5.5

Fasting glucose (mmol/l) 5.53 ± 1.42 6.16 ± 1.96 5.94 ± 1.34

HbA1c (%) 5.90 ± 0.96 6.08 ± 1.22 5.66 ± 0.69

Fasting insulin (pmol/l) 84.0 (61.8-114.0) 80.4 (57.5-110.4) 51.8 (37.3-72.8)

HOMA-B (%) 114.6 (90.0-147.7) 97.4 (72.7-122.4) 69.0 (51.8-91.0)

HOMA-S (%) 63.4 (46.9-85.1) 64.2 (47.3-89.6) 99.0 (72.0-138.0)

Body mass index (kg/m2) 23.6 ± 3.3 25.2 ± 3.7 23.3 ± 2.9

Waist circumference (cm) 81.6 ± 10.3 85.8 ± 10.4 81.8 ± 9.1

Waist-hip ratio 0.89 0.07 0.90 0.08 0.87 ± 0.07

Normal fasting glucose, n (%) 1,183 (72.4) 725 (46.0) 308 (41.1)

Impaired fasting glucose, n (%) 299 (18.3) 579 (36.8) 368 (49.13)

Type 2 Diabetes, n (%) 152 (9.3) 272 (17.3) 73 (9.8)

Among T2D cases from the NHAPC study, 232 (87 from Shanghai and 145 from Beijing) were receiving glucose-lowering treatment, while all T2D cases from GMOS were treatment-naive patients. Data are presented as number (percentage), means ± SD or medians (inter quartile range).

SUPPLEMENTARY DATA


Supplementary Table 11. Associations with T2D-related quantitative traits in the NHAPC and the GMOS studies.

Variables Glucose (mmol/L)

HbA1C (%)

Insulin* (pmol/L)

HOMA-B* (%)

HOMA-S* (%)

BMI (kg/m2)

WC (cm)

WHR

GRK5-rs10886471 (T/C)

NFG+IFG+T2D (N=3,581)

Beta 0.0162 0.0301 0.0349 0.0219 -0.0355 0.1276 0.1035 0.0020

P 0.6616 0.1955 0.0204 0.0882 0.0155 0.1871 0.7172 0.3203

NFG (N=2,138)

Beta -0.0030 0.0157 0.0449 0.0312 -0.0434 0.0517 -0.1741 0.0005

P 0.8277 0.2807 0.0169 0.0194 0.0165 0.6741 0.6324 0.8303

RASGRP1-rs7403531 (T/C)


Beta 0.0732 0.0386 -0.0191 -0.0331 0.0181 -0.0154 0.0376 -0.0012

P 0.0213 0.0538 0.1424 0.0027 0.1522 0.8536 0.8788 0.4930

NFG (N=2,138)

Beta 0.0142 0.0276 -0.0289 -0.0269 0.0296 -0.0731 -0.0272 -0.0020

P 0.2435 0.0300 0.0772 0.0209 0.0610 0.4933 0.9315 0.3630

CDC123-rs11257655 (C/T)


Beta 0.0171 0.0233 -0.0120 -0.0155 0.0089 0.0462 0.2164 0.0022

P 0.5816 0.2310 0.3443 0.1499 0.4726 0.5692 0.3675 0.1833

NFG (N=2,139)

Beta -0.0010 0.0267 -0.0136 -0.0102 0.0151 0.1165 0.3149 0.0025

P 0.9301 0.0283 0.3861 0.3639 0.3208 0.2554 0.2998 0.2292

HNF1B-rs4430796 (G/A)


Beta 0.0468 0.0205 -0.0474 -0.0442 0.0424 -0.0683 -0.2798 -0.0026

P 0.1502 0.3244 6.10E-04 1.50E-04 0.0016 0.4438 0.2882 0.1501

NFG (N=2,134)

Beta 0.0014 0.0092 -0.0635 -0.0417 0.0590 -0.1034 -0.4090 -0.0028

P 0.9115 0.4976 2.80E-04 8.08E-04 4.76E-04 0.3647 0.2262 0.2356

DUSP9-rs5945326 (G/A)


Beta 0.1215 0.0582 -0.0085 -0.0368 0.0061 0.0355 0.0638 0.0007

P 2.28E-06 3.11E-04 0.4223 4.16E-05 0.5523 0.6003 0.7502 0.5969

NFG (N=2,132)

Beta 0.0087 -0.0059 -0.0166 -0.0143 0.0165 0.0193 -0.1079 -0.0009

P 0.3840 0.5697 0.2125 0.1316 0.1979 0.8238 0.6745 0.6037

As associations of risk variants at CDKAL1, KCNQ1, CDKN2A/B, and GLIS3 with T2D-related quantitative traits in individuals from the NHAPC study have been reported in our previous studies (22-24), we performed association testing only for GRK5, RASGRP1, CDC123, HNF1B, and DUSP9 loci, in whole samples (NFG+IFG+T2D), in which the 224 T2D cases receiving glucose-lowering treatments were excluded, or in NFG samples only. Each of the association analyses were performed in Shanghai and Beijing subpopulations separately, and results were then combined by fixed-effect inverse variance weighted meta-analysis. Linear regression model was used for association analysis, adjusted for age, sex, and study covariates (NHAPC and GMOS, for Shanghai samples only) under an additive genetic model. *Traits values for insulin, HOMA-B, and HOMA-S were natural log transformed before analysis. Alleles are presented as minor allele/major allele and alleles underlined are risk alleles for T2D. The beta coefficient is reported for risk-allele of each SNP. Associations showing nominal significance at P < 0.05 are highlighted in grey. NFG: normal fasting glucose, IFG: impaired fasting glucose , WC: waist circumference, WHR, waist-hip ratio.

SUPPLEMENTARY DATA


Supplementary Table 12. Relative mRNA expression levels of GRK5

Groups GRK5-rs10886471(T/C) P for genotype TT+TC CC All

T2D case 1.100+0.165(11) 1.637+0.255(19) 1.440+0.177(30) Control 0.851+0.184(13) 1.107+0.174(20) 0.998+0.124(34) Total 0.965+0.125(24) 1.365+0.157(39) 1.205+0.109(64) 0.02 P for GRK5 gene 0.0048 We measured the relative expression levels of GRK5, the only gene in the LD block of rs10886471, in blood samples from 30 T2D cases (TT/n= 3; TC/n = 8; CC/n = 19), and 34 non-diabetic controls (TT/n = 2; TC/n = 11; CC/n = 20 (one missing data)). Data are presented as mean ± SEM (sample size). Values of the GRK5 relative expression levels were natural log-transformed before analysis. The one-tailed P values are presented.

SUPPLEMENTARY DATA


Supplementary Table 13. The comparison of association results for T2D-associated SNPs at two novel loci between the stage 1 and the DIAGRAM GWAS meta-analysis.

SNP Position (bp)

Alleles (R/A)

Method

RAF r2 with index SNP Stage 1 DIAGRAM+

Controls* CHB† JPT† CEU† CHB† CEU† OR [95% CI] P OR [95% CI] P

chr10:121.06M-121.24M (GRK5-rs10886471)

rs1556714 121,067,181 T/G genotyped 0.91 0.88 0.92 0.87 0.14 0.05 1.31 [1.10-1.57] 2.65E-03 0.95 [0.90-1.00] 6.67E-02

rs4531379 121,068,691 G/A imputed 0.91 0.88 0.92 0.89 0.14 0.06 1.32 [1.11-1.58] 2.08E-03 0.96 [0.90-1.02] 1.41E-01

rs2420617 121,096,397 G/A imputed 0.93 0.93 0.97 0.96 0.36 0.03 1.34 [1.10-1.63] 4.06E-03 0.87 [0.77-0.99] 3.41E-02

rs12415832 121,102,317 C/A imputed 0.93 0.93 0.97 0.99 0.36 0.01 1.34 [1.10-1.63] 4.05E-03 0.85 [0.71-1.02] 7.28E-02

rs17098766 121,106,202 A/G genotyped 0.93 0.94 0.97 0.98 0.36 0.02 1.32 [1.08-1.60] 5.53E-03 0.85 [0.71-1.01] 7.17E-02

rs1413582 121,122,182 T/C genotyped 0.75 0.74 0.72 0.39 0.54 0.55 1.13 [1.01-1.27] 2.98E-02 1.02 [0.98-1.07] 2.60E-01

rs7915681 121,123,378 T/A imputed 0.97 0.99 0.98 0.99 0.06 0.01 1.41 [1.06-1.88] 1.97E-02 0.98 [0.75-1.28] 8.78E-01

rs6585546 121,129,321 T/C genotyped 0.77 0.75 0.72 0.37 0.62 0.65 1.17 [1.05-1.31] 6.56E-03 1.01 [0.97-1.05] 5.88E-01

rs17098821 121,133,557 A/G imputed 0.21 0.20 0.18 0.06 0.06 0.06 1.13 [1.01-1.27] 3.71E-02 0.99 [0.91-1.07] 7.65E-01

rs12573657 121,133,569 G/A imputed 0.97 0.99 0.98 0.97 0.06 0.02 1.46 [1.09-1.95] 1.22E-02 1.08 [0.97-1.21] 1.60E-01

rs12416565 121,134,185 C/G imputed 0.21 0.21 0.20 0.21 0.06 0.39 1.13 [1.01-1.27] 3.73E-02 1.01 [0.97-1.07] 5.69E-01

rs10886471 121,139,393 C/T genotyped 0.76 0.79 0.74 0.48 - - 1.29 [1.15-1.45] 1.48E-05 0.98 [0.94-1.02] 3.52E-01


rs11198903 121,140,973 G/A imputed 0.20 0.20 0.20 0.04 0.06 0.06 1.12 [1.00-1.26] 4.74E-02 0.99 [0.91-1.07] 7.49E-01

rs4752300 121,155,606 G/A imputed 0.75 0.78 0.76 0.39 0.78 0.41 1.22 [1.09-1.37] 6.00E-04 NA [NA-NA] NA

rs12220362 121,157,120 G/T imputed 0.26 0.26 0.26 0.08 0.06 0.02 1.16 [1.04-1.30] 6.81E-03 0.95 [0.89-1.02] 1.71E-01

rs4752301 121,161,742 T/A imputed 0.77 0.86 0.76 0.51 0.55 0.78 1.16 [1.03-1.30] 1.11E-02 0.96 [0.92-1.01] 9.65E-02

rs2420620 121,162,816 C/G imputed 0.77 0.86 0.76 0.51 0.55 0.74 1.16 [1.04-1.30] 1.02E-02 0.96 [0.92-1.01] 9.15E-02


rs4752305 121,166,591 C/T genotyped 0.77 0.82 0.79 0.48 0.55 0.71 1.17 [1.04-1.31] 7.78E-03 0.96 [0.92-1.00] 5.58E-02

rs11198918 121,172,570 C/T imputed 0.20 0.23 0.18 0.06 0.05 0.01 1.14 [1.02-1.27] 2.65E-02 0.98 [0.90-1.06] 5.89E-01

chr15:36.60M-36.71M (RASGRP1-rs107403531)

rs11073332 36,604,906 C/T genotyped 0.38 0.35 0.47 0.36 0.90 0.62 1.19 [1.08-1.31] 5.01E-04 1.05 [1.01-1.10] 2.29E-02

rs7403047 36,610,084 C/A imputed 0.27 0.23 0.36 0.06 0.59 0.13 1.27 [1.13-1.42] 6.83E-05 1.06 [0.97-1.17] 1.95E-01

SUPPLEMENTARY DATA


rs7403531 36,610,197 T/C genotyped 0.34 0.32 0.45 0.28 - - 1.21 [1.10-1.34] 1.55E-04 1.06 [1.01-1.11] 2.25E-02

rs8043085 36,615,432 T/G imputed 0.36 0.32 0.47 0.29 0.90 0.75 1.24 [1.12-1.38] 6.15E-05 1.07 [1.02-1.13] 3.82E-03

rs12593201 36,631,398 A/G imputed 0.38 0.33 0.48 0.31 0.81 0.68 1.25 [1.12-1.38] 4.13E-05 1.07 [1.03-1.12] 2.40E-03

rs12324139 36,654,501 G/A imputed 0.55 0.58 0.63 0.51 0.17 0.34 1.15 [1.04-1.26] 6.09E-03 1.01 [0.97-1.05] 5.87E-01

rs12595375 36,655,729 A/C imputed 0.55 0.58 0.63 0.79 0.17 0.04 1.14 [1.04-1.26] 6.27E-03 1.01 [0.96-1.06] 6.84E-01

rs13329072 36,656,080 A/C imputed 0.33 0.32 0.41 0.54 0.19 0.20 1.15 [1.04-1.28] 6.84E-03 0.96 [0.92-1.00] 7.28E-02




Among the SNPs at the two novel loci, only those associated with T2D at P < 0.05 in the discovery stage were selected for lookup in the DIAGRAM+ GWAS meta-analysis, and all proxy SNPs (r2 > 0.9 in HapMap CEU population) for each of the searched SNPs were filtered out. Index SNPs at the two loci are highlighted in grey. *non-diabetic controls in stage 1. †Samples in HapMap. R/A: Risk allele/Alternative allele, RAF: Risk allele frequency, NA: not available, DIAGRAM+: current version of data set from the DIAGRAM consortium, comprising up to 8,130 T2D cases and 38,987 controls

SUPPLEMENTARY DATA


Supplementary Table 14. Comparison of LD structure between populations Region Index SNP Nearest Gene CHB-CEU CHB-JPT

chr10:121.06M-121.24M rs10886471 GRK5 0.0432 0.909

chr15:36.60M-36.71M rs7403531 RASGRP1 0.0043 0.101

Results are given as Monte-Carlo P values generated from varLD algorithm by comparing pairwise r2 of SNPs in each genomic region between Chinese Hans (CHB panel) and Europeans (CEU panel) and Japanese (JPT panel) from HapMap2. Supplementary Table 15. Associations of T1D or LADA susceptibility loci with T2D in stage 1

SNP CHR Reported Gene/Region

References

Stage 1

Method Alleles (R/A)

OR [95% CI] P

rs2269241 1 PGM1 (25) imputed T/C 1.10 [0.98-1.24] 1.14E-01

rs2476601 1 PTPN22 (25) NA NA NA [NA-NA] NA

rs2488457 1 PTPN22 (26) imputed G/C 1.02 [0.93-1.13] 6.32E-01

rs2816316 1 RGS1 (27) genotyped C/A 1.01 [0.89-1.14] 8.63E-01

rs3024505 1 IL10 (25) genotyped A/G 1.09 [0.83-1.38] 4.72E-01

rs1534422 2 2p25.1 (25) genotyped G/A 1.11 [0.99-1.25] 5.48E-02

rs2165738 2 2p23.3 (28) imputed C/G 1.01 [0.92-1.13] 7.94E-01

rs478222 2 EFR3B (29) imputed A/T 1.03 [0.94-1.14] 4.98E-01

rs6547853 2 FOSL2 (29) NA NA NA [NA-NA] NA

rs9653442 2 AFF3 (30) imputed T/C 1.05 [0.95-1.16] 3.06E-01

rs917997 2 IL18RAP (27) genotyped C/T 1.04 [0.94-1.14] 4.06E-01

rs1990760 2 IFIH1 (30) genotyped C/T 1.00 [0.89-1.13] 9.98E-01

rs3747517 2 IFIH1 (31) genotyped C/T 1.03 [0.93-1.14] 5.96E-01

rs7574865 2 STAT4 (32) genotyped T/G 1.05 [0.95-1.16] 3.84E-01

rs3087243 2 CTLA4 (28) imputed A/G 1.03 [0.91-1.16] 6.33E-01

rs11711054 3 CCR5 (25; 27) genotyped G/A 1.11 [1.01-1.23] 4.30E-02

rs10517086 4 4p15.2 (25) genotyped G/A 1.11 [0.66-1.86] 6.94E-01

rs4505848 4 IL2 (28; 30) genotyped A/G 1.02 [0.93-1.12] 6.97E-01

rs6897932 5 IL7R (30) genotyped C/T 1.00 [0.88-1.14] 9.67E-01

rs1048709 6 HLA (33-36) imputed G/A 1.05 [0.96-1.17] 3.89E-01

rs630379 6 HLA (33-36) genotyped C/A 1.07 [0.98-1.18] 2.37E-01

rs9267992 6 HLA (25) genotyped G/A 1.21 [0.78-1.76] 3.22E-01

rs926070 6 HLA (25) genotyped A/G 1.02 [0.89-1.15] 6.99E-01

rs3129941 6 HLA (37) genotyped A/G 1.06 [0.89-1.24] 4.20E-01

rs9268645 6 HLA (37; 38) imputed C/G 1.01 [0.92-1.12] 7.71E-01

rs9268831 6 HLA (37; 39) imputed C/T 1.03 [0.93-1.14] 5.07E-01

rs660895 6 HLA (33-36) genotyped A/G 1.01 [0.90-1.14] 8.04E-01

rs9272346 6 HLA (28) imputed A/G 1.01 [0.92-1.12] 8.04E-01

rs2187668 6 HLA (33-36) genotyped T/C 1.01 [0.82-1.23] 9.58E-01

rs9273363 6 HLA (37; 38) imputed C/A 1.06 [0.95-1.18] 2.82E-01

rs439121 6 HLA (39) NA NA NA [NA-NA] NA

SUPPLEMENTARY DATA


rs11755527 6 BACH2 (28) imputed G/C 1.06 [0.95-1.17] 2.39E-01

rs9388489 6 C6orf173 (25) genotyped A/G 1.10 [0.78-1.55] 5.88E-01

rs10499194 6 TNFAIP3 (29; 32) imputed T/C 1.00 [0.78-1.28] 9.83E-01

rs237025 6 SUMO4 (40) imputed A/G 1.02 [0.92-1.13] 6.85E-01

rs1738074 6 TAGAP (27) genotyped C/T 1.00 [0.92-1.10] 9.52E-01

rs924043 6 6q27 (29) genotyped C/T 1.03 [0.92-1.14] 5.35E-01

rs7804356 7 SKAP2 (25) genotyped C/T 1.15 [0.99-1.33] 6.10E-02

rs550448 7 LOC100128081 (29) NA NA NA [NA-NA] NA

rs4948088 7 COBL (25) NA NA NA [NA-NA] NA

rs12679857 8 TNFRSF11B (29) imputed G/A 1.04 [0.94-1.14] 4.73E-01

rs7020673 9 GLIS3 (25) imputed G/C 1.15 [1.06-1.26] 4.03E-03

rs2104286 10 CD25 (38) genotyped C/T 1.04 [0.89-1.19] 6.27E-01

rs12251307 10 IL2RA (28; 41) genotyped C/T 1.06 [0.94-1.19] 2.93E-01

rs11258747 10 PRKCQ (28) imputed G/T 1.07 [0.85-1.36] 6.06E-01

rs10509540 10 C10orf59 (25) genotyped C/T 1.00 [0.90-1.12] 9.76E-01

rs3842755 11 INS (33-36) NA NA NA [NA-NA] NA

rs7111341 11 INS (25; 42) genotyped T/C 1.20 [1.00-1.43] 3.09E-02

rs4763879 12 CD69 (25; 38) genotyped A/G 1.05 [0.96-1.16] 2.84E-01

rs1701704 12 12q13.2 (43) genotyped T/G 1.05 [0.93-1.17] 3.99E-01

rs2292239 12 ERBB3 (30; 43) imputed G/T 1.08 [0.95-1.22] 2.06E-01

rs1678536 12 12q13.3 (44) imputed C/G 1.14 [0.98-1.31] 4.98E-02

rs10877012 12 CYP27B1 (45) NA NA NA [NA-NA] NA

rs3184504 12 SH2B3 (27; 30) NA NA NA [NA-NA] NA

rs17696736 12 C12orf30 (28; 30) NA NA NA [NA-NA] NA

rs539514 13 LMO7 (29) imputed T/A 1.05 [0.80-1.36] 7.38E-01

rs9585056 13 GPR183 (46) imputed T/C 1.32 [1.06-1.68] 2.06E-02

rs1465788 14 14q24.1 (25) genotyped C/T 1.14 [1.03-1.27] 1.23E-02

rs4900384 14 14q32.2 (25) genotyped A/G 1.01 [0.91-1.11] 9.12E-01

rs941576 14 DLK1 (47) imputed A/G 1.02 [0.92-1.13] 7.40E-01

rs17574546 15 RASGRP1 (48) imputed C/A 1.16 [0.89-1.54] 2.92E-01

rs3825932 15 CTSH (28) imputed T/C 1.05 [0.88-1.23] 5.70E-01

rs725613 16 KIAA0350 (49) genotyped T/G 1.00 [0.90-1.12] 9.59E-01

rs12708716 16 KIAA0350 (30; 42) imputed A/G 1.01 [0.90-1.13] 8.53E-01

rs416603 16 C16orf75, PRM3, TNP2 (28) imputed A/T 1.01 [0.88-1.16] 9.05E-01

rs12444268 16 16p12.3 (25) NA NA NA [NA-NA] NA

rs4788084 16 IL27 (25) genotyped C/T 1.06 [0.95-1.18] 2.52E-01

rs7202877 16 16q23.1 (25) genotyped T/G 1.01 [0.89-1.13] 9.21E-01

rs16956936 17 17p13.1 (25) NA NA NA [NA-NA] NA

rs2290400 17 ORMDL3 (25) genotyped T/C 1.05 [0.94-1.17] 3.49E-01

rs7221109 17 17q21.2 (25) imputed T/C 1.01 [0.90-1.13] 8.89E-01

rs1893217 18 PTPN2 (30) genotyped A/G 1.06 [0.92-1.19] 3.78E-01

rs763361 18 CD226 (30) genotyped C/T 1.07 [0.97-1.18] 1.80E-01

rs2304256 19 TYK2 (47) NA NA NA [NA-NA] NA

rs425105 19 19q13.32 (25) genotyped T/C 1.05 [0.93-1.19] 4.33E-01

rs2281808 20 20p13 (25) imputed C/T 1.11 [0.98-1.26] 1.18E-01

SUPPLEMENTARY DATA


rs11203203 21 UBASH3A (25) genotyped G/A 1.05 [0.82-1.33] 7.08E-01

rs5753037 22 22q12.2 (25) genotyped C/T 1.07 [0.97-1.17] 1.92E-01

rs229541 22 C1QTNF6 (28) imputed G/A 1.01 [0.91-1.12] 8.97E-01

rs2664170 X Xq28 (25) genotyped A/G 1.04 [0.94-1.15] 4.75E-01

LADA: latent autoimmune diabetes in adults, R/A: Risk allele/Alternative allele, NA: not available.

SUPPLEMENTARY DATA


Supplementary Figure 1. Results of principle component analysis of samples in stage 1 GWAS with HapMap reference. HapMap reference: HapMap 3 panels of 112 CEU, 147 YRI, 137 CHB and 113 JPT individuals. Plots were generated based on the first two eigenvectors from PCA. (A,B) Samples from Shanghai and Beijing in stage 1 GWAS are represented by red dots and blue dots respectively.

A B

SUPPLEMENTARY DATA


Supplementary Figure 2. Results of principle component analysis of samples in stage 1 GWAS without HapMap reference. Plots were generated based on the first two eigenvectors from PCA; (A) Samples from Shanghai and Beijing in stage 1 GWAS are represented by red dots and blue dots respectively; (B) T2D cases and non-diabetic controls in stage 1 GWAS are represented by red dots and blue dots respectively.

A B

SUPPLEMENTARY DATA


Supplementary Figure 3. Quantile-Quantile plot for genome-wide association analysis of SNPs in 3,712 samples in stage 1. Results of Model 1 were from pooled analysis, adjusting for age, sex, and the first two principle components. Results of Model 2 were from pooled analysis, adjusting for age, sex, BMI, and the first two principle components. The Genomic control inflation factor (λ) for each model is presented in the figure. (A) Plot was generated by using only 495,686 genotyped SNPs. (B) Plot was generated by using both genotyped and imputed SNPs.

A B

SUPPLEMENTARY DATA


Supplementary Figure 4. Manhattan plot for GWA analysis of both genotyped and imputed SNPs in stage 1 samples. The –log10P values from pooled analysis, adjusting for age, sex, and the first two principle components are presented in the figure. The red dots at each locus indicate the signals with P < 10−6.

SUPPLEMENTARY DATA


Supplementary Figure 5. Regional plots of 2 novel T2D loci. P values of genotyped and imputed SNPs were from pooled analysis, adjusting for age, sex, and the first two principle components in stage 1 samples. Imputed SNPs were estimated by MACH software (see URLs) using LD information from 194 Asians in 1000 Genome 2010.08 release as references. The conditional analysis was performed by further adjusting for tested SNPs, which were genotyped in stage 2, in each plotted region. The regional plots for the 500kb region centered on index SNPs were generated by plotting the –log10 P values of SNPs against their genomic position (NCBI Build 37). The positions of genes were annotated from the UCSC Genome Browser by using GRCh37 assembly. The index SNPs are purple colored. Other SNPs are colored according to their LD (r2) with the index SNP from 1000 Genome ASN. The recombination rate is shown as a light blue line to reflect the local LD structure.

SUPPLEMENTARY DATA


Supplementary Figure 6. Linkage disequilibrium mapping of GRK5. Parirwise correlation structure was analyzed by Haploview. The plot includes pairwise D’ values from the HapMap release 27 for the CEU, CHB and JPT. The region used for comparison of regional LD patterns between populations is highlighted in a blue box.

SUPPLEMENTARY DATA


Supplementary Figure 7. Linkage disequilibrium mapping of RASGRP1. Parirwise correlation structure was analyzed by Haploview. (A) The plot includes pairwise D’ values from the HapMap release 27 for the CEU, CHB and JPT. The region used for comparison of regional LD patterns between populations is highlighted in a blue box. (B) r2 values among 4 SNPs, including two T2D SNPs (rs7403531 and rs12593201) and two reported T1D SNPs (rs7171171 and rs17574546).

A

SUPPLEMENTARY DATA


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3. Jia WP, Pang C, Chen L, Bao YQ, Lu JX, Lu HJ, Tang JL, Wu YM, Zuo YH, Jiang SY, Xiang KS: Epidemiological characteristics of diabetes mellitus and impaired glucose regulation in a Chinese adult population: the Shanghai Diabetes Studies, a cross-sectional 3-year follow-up study in Shanghai urban communities. Diabetologia 2007;50:286-292

4. Hu C, Wang C, Zhang R, Ng MC, Bao Y, So WY, Ma RC, Ma X, Chan JC, Xiang K, Jia W: Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population. Diabetologia 2010;53:290-298

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35. Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC, Walker M, Gillespie KM, Bingley PJ, Hitman GA, Holman RR, McCarthy MI, Clark A: An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia 2007;50:68-73

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