Introduction

Adiponectin is a highly abundant adipocyte-derived plasma protein whose levels correlate inversely with a range of important clinical parameters including blood glucose, indices of insulin resistance, proatherogenic dyslipidemia, and risk of type 2 diabetes (T2D), stroke and coronary artery disease [1], [2], [3], [4]. Collectively these conditions account for most of the burgeoning pandemic of obesity-related morbidity and mortality that poses a severe and global healthcare challenge [5]. Murine studies suggest that adiponectin plays a mediating role in at least some of these obesity-related complications, and although less clearly established in humans, this suggests that understanding the pathophysiology of adiponectin may uncover novel therapeutic targets in major, highly prevalent human disease.[6], [7].

Twins and family studies have revealed moderate to high estimates of heritability (30–70%) for plasma adiponectin levels [8], [9], [10], [11]. However, until recently, few genes associated with adiponectin levels have been identified. Candidate and genome-wide association studies (GWAS) have shown pronounced associations between common polymorphisms in the adiponectin gene (ADIPOQ) and adiponectin levels [12], [13], [14], [15]. A recent meta-analysis of three GWAS for adiponectin levels identified variants in a novel candidate gene, ARL15, that were associated with adiponectin levels, coronary heart disease (CHD), T2D and other metabolic traits [16]. Furthermore, CDH13 and KNG1 genes were found to be associated with adiponectin levels in two studies involving East Asian populations [17], [18]. Although part of the variance explained by the ADIPOQ locus, most of the heritability of adiponectin levels remains unaccounted for. Therefore, we sought to identify novel common variants influencing adiponectin levels and test their association with risk of T2D and related metabolic traits within the framework of a large multi-ethnic consortium of GWAS.

We combined genome-wide association results of 35,355 individuals from three different ethnicities (white Europeans (n = 29,347), African American s(n = 4,232) and East Asians (n = 1,776)), applying a novel meta-analytic method to allow for heterogeneity in allelic effects between populations of different ethnic backgrounds. We next examined whether identified genome-wide significant single nucleotide polymorphisms (SNPs) also associated with expression of their nearest gene in human adipocytes, the main source of adiponectin. Since adiponectin has been associated with T2D, insulin resistance and metabolic traits we next investigated whether a multi-SNP genotypic risk, comprising genome-wide significant SNPs for adiponectin levels, also influenced risk of T2D and related traits measured in the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM+) [19], Meta-Analysis of Glucose and Insulin Related Traits Consortium (MAGIC) [20], Genetic Investigation of ANthropometric measures Traits (GIANT) [21] , Global Lipids Genetic Consortium (GLGC) [22], and Body Fat GWAS consortia [23].

Results

Results of Meta-Analysis of GWAS

The meta-analysis was divided into four phases 1) Discovery phase, which involved cohorts providing GWAS results, 2) In-silico replication phase which included additional GWAS cohorts joining our meta-analysis after the completion of the discovery phase, 3) De-novo genotyping in cohorts without GWAS genotyping and 4) Multi-Ethnic meta-analysis applying a novel method for complex trait mapping using different ethnicities.

Discovery phase in individuals of white European origin.

The meta-analysis of sex-combined data from 16 GWAS (n = 29,347) of individuals of white European descent identified ten loci associated with adiponectin levels at p≤5.0×10⁻⁸ (Table 1 and Figure 1A and Figure S1, Table S2). These results include the previously described associations with adiponectin at ADIPOQ (rs6810075[T]; ß = 0.06, p-value = 3.60×10⁻⁴¹), KNG1 (rs2062632[T]; ß = 0.05, p-value = 2.52×10⁻¹⁹) on 3q27.3, and CDH13 (rs12922394[T; ß = −0.1, p = 3.16×10⁻¹⁸) on 16q23.3 (Table 1). Furthermore, we identified variants that showed genome-wide significant association in eight novel independent loci including rs9853056 (within the STAB1 gene, rs4282054 (within the NT5DC2 gene), rs13083798 (within the PBRM1 gene), rs1108842 (within the GNL3 gene), rs11235 (within the NEK4 gene), rs2710323 (within the ITIH1 gene), rs3617 (within the ITIH3 gene), and rs2535627 (within 200 Kb of ITIH4 gene) at 3p21.1; rs1597466 (within 1 Mb of TSC22D2 gene) at 3q25.1; rs2980879 (within 1 Mb of TRIB1 gene) at 8q24.13; rs7955516 (within 1.3 Mb PDE3A gene) at 12p12.2; rs601339 (within the GPR109A gene) at 12q24.31; rs6488898 (within the ATP6V0A2 gene), rs7133378 (within the DNAH10 gene), rs7305864 (within the CCDC92 gene), and rs7978610 (within the ZNF664 gene at 12q24.31, which is 1.3 Mb away from GPR109A); rs2925979 (within the CMIP at 16q23.2 gene); and rs731839 (within the PEPD gene) at 19q13.11. (Figure 2A–2E, Table 1).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Figure 1. Manhattan plots for meta-analyses in the discovery phase.

A) Combined sex analysis in European populations, B) Meta-Analysis of Multiple Ethnicities. The Manhattan plots show −Log₁₀ (p-value) measures for association between single nucleotide polymorphisms (SNPs) and chromosomal position. The SNPs that achieved genome-wide significance are highlighted in green.

https://doi.org/10.1371/journal.pgen.1002607.g001

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Figure 2. Regional plots of eight newly discovered genome-wide significant chromosomal regions associated with adiponectin concentrations in European populations.

A) chromosome 16q23.2, B) chromosome 19 q13.11 C) Chromosome 3p21.1, D) two loci on chromosome 12q24.31, E) chromosome 8q24.13, F) chromosome 6p21.1, and G) chromosome 1q41. In each panel, purple diamonds indicate the top SNPs, which have the strongest evidence of association. Each circle shows a SNP with a color scale relating the r² value for that SNP and the top SNP from HapMap CEU. Blue lines indicate estimated recombination rates from HapMap. The bottom panels illustrate the relative position of genes near each locus. Candidate genes are indicated by red ovals.

https://doi.org/10.1371/journal.pgen.1002607.g002

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Lead SNP per Locus for Genome-Wide Significant SNPs Arising from the Sex-Combined Meta-Analysis in European Populations.

https://doi.org/10.1371/journal.pgen.1002607.t001

In our analysis a common variant (rs601339, MAF = 0.18, allele G) downstream of the GPR109A gene (the putative niacin receptor) was associated with adiponectin (ß = 0.04, p = 7.94×10⁻¹⁰) and HDL-C (ß = 0.03, p = 5.59×10⁻⁷) in the global lipid analysis. In a coincident candidate gene analysis 11 SNPs were typed in GPR109A/B in CoLaus and LOLIPOP cohorts, containing individuals of European descent. A single nominally significant coding SNP R311C (rs7314976, MAF = 0.14) within the GPR109A gene was taken forward for replication and found to be consistently associated with adiponectin in the three cohorts (CoLaus, Fenland and MRC Ely study, n = 8285, p = 4.6×10⁻⁸) and HDL-cholesterol (HDL-C) in four cohorts (CoLaus, Fenland, Ely study and Lolipop, n = 18425, p = 2.9×10⁻⁸) (Figure S2A, S2B). However R311C and rs601339 were not in linkage disequilibirium with each other (r2 = 0.04). Therefore the two variants represent two independent signals from the same locus but with similar effects on HDL-cholesterol and adiponectin.

In silico follow-up phase.

In the in-silico follow-up phase 468 SNPs demonstrating genome-wide significant (p<5×10⁻⁸ ) or suggestive (p<5×10⁻⁶) association with adiponectin in the discovery phase were tested for association in additional European cohorts. (Table S3). These SNPs were tested in seven additional GWAS datasets (n = 6,623 from NHS, HPFS, HABC, ERF2, LLS, GARP and ARIC studies) and the combined meta-analysis of the discovery and follow-up in-silico GWAS datasets detected additional loci on chromosomes 1q41 near the LYPLAL1 gene (rs3001032, p = 3.6×10⁻⁸) and chromosome 6p21.1 near the VEGFA gene (rs998584, p = 5.8×10⁻¹²) that reached genome-wide significance. While we confirmed seven loci that had reached genome-wide significance at the discovery stage (Table 1, Figure 2F and 2G, Table S2), two identified loci (3q25.1 and 12q24.31) did not remain genome-wide significant in the joint analysis of discovery and follow-up results.

De novo follow-up phase.

Next, in the de-novo genotyping follow-up phase, we genotyped 10 SNPs with suggestive evidence of association (5×10⁻⁸<p<5×10⁻⁶) from the meta-analysis of the discovery and in-silico follow-up phases in an additional 3,913 individuals. Meta-analyzing the discovery and 2 follow-up stages identified a SNP in ARL15 (rs6450176 [G]; ß = 0.026, p = 5.8×10⁻⁸), which was initially described in a previous GWAS for adiponectin levels (Table S3) [16].

Multi-ethnic meta-analysis.

To identify loci influencing adiponectin levels in non-European individuals we performed an additional analysis in 4,232 individuals from an African American population and 1,776 individuals from an East Asian population. In the African American populations, only associations at the ADIPOQ locus reached genome-wide significance, while in the East Asian population there was evidence of association at the ADIPOQ and CDH13 loci (Table S4). Subsequently, we performed a meta-analysis that combined all available GWAS including those of white European origin, African American and East Asian ancestry using novel method MANTRA [24]. This analysis identified two additional loci in or near IRS1 gene on 2q36.3 and at 6q24.1 within a gene desert. (Table 2, Figure 1B).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Genome-Wide Significant SNPs from the Sex-Combined Multi-Ethnic Meta-Analysis.

https://doi.org/10.1371/journal.pgen.1002607.t002

Secondary GWAS analyses.

We next performed meta-analysis of the GWAS data in women (n = 16,685) and men (n = 12,662) separately (Figure S2A, S2B, Tables S5 and S6). Although no novel loci reached genome-wide significance in women or men separately, three loci (chromosome 3p, 8 and 12) associated with adiponectin levels in the sex-combined analysis showed evidence of association (p value<5×10−8) in women (Figure S3). Since different assays were used to measure adiponectin levels, we next tested whether stratification by assay rendered similar results and found the results were highly concordant with the combined analysis. GWAS for high molecular weight adiponectin in the CHS study (n = 2,718) identified 2 SNPs in ADIPOQ (rs17300539, p = 3.0×10⁻¹⁶) and CMIP (rs2927307, p = 2.7×10⁻⁸). These two genes are located within the loci identified in our discovery meta-analysis of adiponectin levels.

Gene Expression Studies

Through gene expression studies we sought to address two questions: First, are any of the SNPs that were genome-wide significant for adiponectin levels associated with expression of their nearest transcripts (cis-eQTLs) and second, whether mRNA levels of loci identified through the GWAS for adiponectin levels are associated with circulating adiponectin levels. To address the first question, we examined whether SNPs within 1 Mb of the SNPs achieving genome-wide significance in the discovery stage were associated with the expression levels of nearby genes in human adipocytes from 776 participants of the MuTHER Consortium [25]. We identified 74 SNPs in three eQTLs to be associated with the expression of five genes in adipocytes, using an array-wide level of statistical significance for eQTLs (P<5.1×10⁻⁵. See Materials and Methods for details). These genes included: NT5DC2 on chromosome 3; CCDC92, GPR109A, and ZNF664 on chromosome12; and PEPD on chromosome 19 (Table 3). The cis-eQTL SNPs often are proxies for the lead SNPs from the GWAS, however, this relationship may also be influenced through mechanisms that are independent from gene expression, such as gene function.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. The Association of Lead Genome-Wide Significant SNPs for Adiponectin with mRNA Levels of Their Nearest Gene.

https://doi.org/10.1371/journal.pgen.1002607.t003

We next identified that mRNA levels of 18 genes arising from six candidate loci were correlated with circulating adiponectin levels (Table 4). Since circulating adiponectin levels may be associated with a surplus of adipocyte transcripts we next tested for enrichment of signal from the candidate loci. There were 133 transcripts in the identified candidate regions, of which 8.2% (11/133) were associated with adiponectin levels at an array-wide level of significance (p<2×10⁻⁶), while 7.5% of the 24k probes on the entire array exceeded the same p-value threshold, indicating there was therefore no additional enrichment of signal at these candidate loci.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 4. The Association of mRNA Levels from Genes in Candidate Loci in Human Adipocytes with Circulating Adiponectin Levels.

https://doi.org/10.1371/journal.pgen.1002607.t004

T2D and Metabolic Traits

Using data from several large-scale GWAS consortia, some of the significantly associated variants identified here demonstrated associations with T2D and its related traits (Table S7A, S7B, S7C, and S7D). Several individual SNPs showed evidence for association with T2D and various metabolic traits after accounting for the number of statistically independent SNPs (p-value threshold of 5×10⁻⁴) among the SNPs that were genome-wide significant for adiponectin. These include associations with HDL-C (n = 104 SNPs), triglycerides (TG) (n = 65 SNPs), total cholesterol (TC, n = 12 SNPs), LDL-cholesterol (LDL–C, n = 11 SNPs), and waist-hip ratio (WHR) (n = 65 SNPs) [26]. (However, we note that since sample sizes are different across different consortia power to identify associations is not consistent.) Among these, coding and intronic variants in STAB1 and NT5DC2 genes were associated with WHR and HDL-C, while the variants 1 Mb near TRIB1 were associated with all lipid traits. The coding and intronic variants ariants in the locus on chromosome 12 harboring ZNF664, CCDC92, and DNAH10 showed evidence of association with WHR, HDL-C, and TG. Finally, variants in the PEPD gene were associated with TG.

We next calculated a multi-SNP genotypic risk score based genome-wide significant SNPs from the discovery phase. This multi-SNP genotypic risk score explained 5% of the variance of natural log-transformed adiponectin levels. We then tested the association of this risk score with risk of T2D and metabolic related traits. The multi-SNP genotypic risk score was associated with increased risk for T2D (ß = 0.3, p = 4.3×10⁻³), where ß is the average additive effect of adiponectin-decreasing risk alleles on the log odds ratio of T2D), increased TG (ß = 0.25, p = 2.6×10⁻¹⁴), increased WHR adjusted for BMI (ß = 0.18, p = 1.8×10⁻⁵), increased post-prandial glucose (ß = 0.25, p = 0.01), increased fasting insulin (ß = 0.05, p = 0.01), homeostatic model assessment- insulin resistance (HOMA-IR) (ß = 0.04, p = 0.047), and with lower HDL-C concentrations (ß = −0.24, p = 4.5×10⁻¹³) and decreased BMI (ß = −0.16, p = 1.4×10⁻⁴). (Table 5).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 5. Results of Association of Multi-SNP Genotypic Risk Score with Diabetes and Related Traits.

https://doi.org/10.1371/journal.pgen.1002607.t005

Discussion

In this comprehensive multi-ethnic analysis of the genetic influences on adiponectin levels and their impact on metabolic traits and T2D, we have identified 10 novel loci and confirmed the associations of variants in the ADIPOQ and CDH13 loci with adiponectin levels. The adiponectin risk alleles were associated with T2D and related metabolic traits such as BMI, WHR, TG, HDL-C, 2-hour glucose, HOMA-IR and fasting insulin. These findings demonstrate that adiponectin, T2D and metabolic syndrome have a shared allelic architecture.

Materials and Methods

Study Design

Our study consisted of three stages. First, in the discovery stage we performed a meta-analysis of the GWAS summary statistics of 16 studies involving 29,347 participants of white European origin to detect SNPs that are associated with adiponectin levels. All signals with p<5×10⁻⁶ were followed up in seven additional cohorts (n = 6,623) with GWAS data (in-silico phase) that later joined the consortium and then a subset of SNPs (n = 10) by de-novo genotyping in 3,913 additional participants from three cohorts (n = 39,883 for the combined analysis in Europeans). We also performed a multi-ethnic meta-analysis by combining summary statistics from the 16 studies of individuals of white European discovery cohorts (n = 29,347) with those of five cohort studies that included African Americans subjects (n = 4,232) and one East Asian cohort (n = 1,776) to obtain a total 35,355 individuals for the GWAS meta-analysis involving different ethnicities. After identifying variation near two genes of pharmaceutical importance (GPR109A and GPR109B), which encode the putative niacin receptors, we typed additional rare coding and tagging variants in a subset of cohorts. Second, we examined whether the identified SNPs of the first stage also associate with mRNA levels of nearest gene(s) expressed using adipose tissue of 776 European women. We also tested for association between adiponectin levels and mRNA levels of the genes in our candidate loci in adipose tissue of a subgroup of 436 individuals [25]. Third, we calculated a multi-SNP genotypic risk score using genome-wide significant adiponectin-lowering alleles and tested the association of this risk score with T2D and related metabolic traits. Figure 3 shows a flow chart detailing the study design.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Figure 3. Flow chart of study design.

https://doi.org/10.1371/journal.pgen.1002607.g003

Supporting Information

Acknowledgments

We thank all study participants, volunteers, and study personnel that made this consortium possible. We would also like to thank Ms. Renee Atallah for her efforts with the writing and correction of the manuscript.

Consortia Authors' list:

DIAGRAM+:

Benjamin F Voight^1,2,3, Laura J Scott⁴, Valgerdur Steinthorsdottir⁵, Andrew P Morris⁶, Christian Dina^7,8, Ryan P Welch⁹, Eleftheria Zeggini^6,10, Cornelia Huth^11,12, Yurii S Aulchenko¹³, Gudmar Thorleifsson⁵, Laura J McCulloch¹⁴, Teresa Ferreira⁶, Harald Grallert^11,12, Najaf Amin¹³, Guanming Wu¹⁵, Cristen J Willer⁴, Soumya Raychaudhuri^1,2,16, Steve A McCarroll^1,17, Claudia Langenberg¹⁸, Oliver M Hofmann¹⁹, Josée Dupuis^20,21, Lu Qi^22–24, Ayellet V Segrè^1,2,17, Mandy van Hoek²⁵, Pau Navarro²⁶, Kristin Ardlie¹, Beverley Balkau^27,28, Rafn Benediktsson^29,30, Amanda J Bennett¹⁴, Roza Blagieva³¹, Eric Boerwinkle³², Lori L Bonnycastle³³, Kristina Bengtsson Boström³⁴, Bert Bravenboer³⁵, Suzannah Bumpstead¹⁰, Noël P Burtt¹, Guillaume Charpentier³⁶, Peter S Chines³³, Marilyn Cornelis²⁴, David J Couper³⁷, Gabe Crawford¹, Alex SF Doney^38,39, Katherine S Elliott⁶, Amanda L Elliott^1,17,40, Michael R Erdos³³, Caroline S Fox^21,41, Christopher S Franklin⁴², Martha Ganser⁴, Christian Gieger¹¹, Niels Grarup⁴³, Todd Green^1,2, Simon Griffin¹⁸, Christopher J Groves¹⁴, Candace Guiducci¹, Samy Hadjadj⁴⁴, Neelam Hassanali¹⁴, Christian Herder⁴⁵, Bo Isomaa^46,47, Anne U Jackson⁴, Paul RV Johnson⁴⁸, Torben Jørgensen^49,50, Wen HL Kao^51,52, Norman Klopp¹¹, Augustine Kong⁵, Peter Kraft^22,23, Johanna Kuusisto⁵³, Torsten Lauritzen⁵⁴, Man Li⁵¹, Aloysius Lieverse⁵⁵, Cecilia M Lindgren⁶, Valeriya Lyssenko⁵⁶, Michel Marre^57,58, Thomas Meitinger^59,60, Kristian Midthjell⁶¹, Mario A Morken³³, Narisu Narisu³³, Peter Nilsson⁵⁶, Katharine R Owen¹⁴, Felicity Payne¹⁰, John RB Perry^62,63, Ann-Kristin Petersen¹¹, Carl Platou⁶¹, Christine Proença⁷, Inga Prokopenko^6,14, Wolfgang Rathmann⁶⁴, N William Rayner^6,14, Neil R Robertson^6,14, Ghislain Rocheleau^65–67, Michael Roden^45,68, Michael J Sampson⁶⁹, Richa Saxena^1,2,40, Beverley M Shields^62,63, Peter Shrader^3,70, Gunnar Sigurdsson^29,30, Thomas Sparsø⁴³, Klaus Strassburger⁶⁴, Heather M Stringham⁴, Qi Sun^22,23, Amy J Swift³³, Barbara Thorand¹¹, Jean Tichet⁷¹, Tiinamaija Tuomi^46,72, Rob M van Dam²⁴, Timon W van Haeften⁷³, Thijs van Herpt^25,55, Jana V van Vliet-Ostaptchouk⁷⁴, G Bragi Walters⁵, Michael N Weedon^62,63, Cisca Wijmenga⁷⁵, Jacqueline Witteman¹³, Richard N Bergman⁷⁶, Stephane Cauchi⁷, Francis S Collins⁷⁷, Anna L Gloyn¹⁴, Ulf Gyllensten⁷⁸, Torben Hansen^43,79, Winston A Hide¹⁹, Graham A Hitman⁸⁰, Albert Hofman¹³, David J Hunter^22,23, Kristian Hveem^61,81, Markku Laakso⁵³, Karen L Mohlke⁸², Andrew D Morris^38,39, Colin NA Palmer^38,39, Peter P Pramstaller⁸³, Igor Rudan^42,84,85, Eric Sijbrands²⁵, Lincoln D Stein¹⁵, Jaakko Tuomilehto⁸⁶, Andre Uitterlinden²⁵, Mark Walker⁸⁷, Nicholas J Wareham¹⁸, Richard M Watanabe^76,88, Goncalo R Abecasis⁴, Bernhard O Boehm³¹, Harry Campbell⁴², Mark J Daly^1,2, Andrew T Hattersley^62,63, Frank B Hu^22–24, James B Meigs^3,70, James S Pankow⁸⁹, Oluf Pedersen^43,90,91, H.-Erich Wichmann^11,12,92, Inês Barroso¹⁰, Jose C Florez^1,2,3,93, Timothy M Frayling^62,63, Leif Groop^56,72, Rob Sladek^65–67, Unnur Thorsteinsdottir^5,94, James F Wilson⁴², Thomas Illig¹¹, Philippe Froguel^7,95, Cornelia M van Duijn¹³, Kari Stefansson^5,94, David Altshuler^{1,2,3,17,40,93}, Michael Boehnke⁴, Mark I McCarthy^6,14,96.

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

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

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.

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

MAGIC Consortium:

Josée Dupuis^1,2,178, Claudia Langenberg^3,178, Inga Prokopenko^4,5,178, Richa Saxena^6,7,178, Nicole Soranzo^8,9,178, Anne U Jackson¹⁰, Eleanor Wheeler¹¹, Nicole LGlazer¹², Nabila Bouatia-Naji¹³, Anna LGloyn⁴, Cecilia MLindgren^4,5, Reedik Mägi^4,5, Andrew P Morris⁵, Joshua Randall⁵, Toby Johnson^14–16, Paul Elliott^17,176, Denis Rybin¹⁸, Gudmar Thorleifsson¹⁹, Valgerdur Steinthorsdottir¹⁹, Peter Henneman²⁰, Harald Grallert²¹, Abbas Dehghan²², Jouke Jan Hottenga²³, Christopher SFranklin²⁴, Pau Navarro²⁵, Kijoung Song²⁶, Anuj Goel^5,27, John R B Perry²⁸, Josephine MEgan²⁹, Taina Lajunen³⁰, Niels Grarup³¹, Thomas Sparsø³¹, Alex Doney³², Benjamin F Voight^6,7, Heather MStringham¹⁰, Man Li³³, Stavroula Kanoni³⁴, Peter Shrader³⁵, Christine Cavalcanti-Proença¹³, Meena Kumari³⁶, Lu Qi³⁷, Nicholas J Timpson³⁸, Christian Gieger²¹, Carina Zabena³⁹, Ghislain Rocheleau^40,41, Erik Ingelsson^42,43, Ping An⁴⁴, Jeffrey O'Connell⁴⁵, Jian'an Luan³, Amanda Elliott^6,7, Steven A McCarroll^6,7, Felicity Payne¹¹, Rosa Maria Roccasecca¹¹, François Pattou⁴⁶, Praveen Sethupathy⁴⁷, Kristin Ardlie⁴⁸, Yavuz Ariyurek⁴⁹, Beverley Balkau⁵⁰, Philip Barter⁵¹, John P Beilby^52,53, Yoav Ben-Shlomo⁵⁴, Rafn Benediktsson^55,56, Amanda J Bennett⁴, Sven Bergmann^14,16, Murielle Bochud¹⁵, Eric Boerwinkle⁵⁷, Amélie Bonnefond¹³, Lori LBonnycastle⁴⁷, Knut Borch-Johnsen^58,59, Yvonne Böttcher⁶⁰, Eric Brunner³⁶, Suzannah J Bumpstead⁸, Guillaume Charpentier⁶¹, Yii-Der Ida Chen⁶², Peter Chines⁴⁷, Robert Clarke⁶³, Lachlan J MCoin¹⁷, Matthew NCooper⁶⁴, Marilyn Cornelis³⁷, Gabe Crawford⁶, Laura Crisponi⁶⁵, Ian NMDay³⁸, Eco J Cde Geus²³, Jerome Delplanque¹³, Christian Dina¹³, Michael R Erdos⁴⁷, Annette CFedson^64,66, Antje Fischer-Rosinsky^67,68, Nita GForouhi³, Caroline SFox^2,69, Rune Frants⁷⁰, Maria Grazia Franzosi⁷¹, Pilar Galan⁷², Mark OGoodarzi⁶², Jürgen Graessler⁷³, Christopher J Groves⁴, Scott Grundy⁷⁴, Rhian Gwilliam⁸, Ulf Gyllensten⁷⁵, Samy Hadjadj⁷⁶, Göran Hallmans⁷⁷, Naomi Hammond⁸, Xijing Han¹⁰, Anna-Liisa Hartikainen⁷⁸, Neelam Hassanali⁴, Caroline Hayward²⁵, Simon CHeath⁷⁹, Serge Hercberg⁸⁰, Christian Herder⁸¹, Andrew A Hicks⁸², David R Hillman^66,83, Aroon DHingorani³⁶, Albert Hofman²², Jennie Hui^52,84, Joe Hung^85,86, Bo Isomaa^87,88, Paul R V Johnson^4,89, Torben Jørgensen^90,91, Antti Jula⁹², Marika Kaakinen⁹³, Jaakko Kaprio^94–96, Y Antero Kesaniemi⁹⁷, Mika Kivimaki³⁶, Beatrice Knight⁹⁸, Seppo Koskinen⁹⁹, Peter Kovacs¹⁰⁰, Kirsten Ohm Kyvik¹⁰¹, GMark Lathrop⁷⁹, Debbie A Lawlor³⁸, Olivier Le Bacquer¹³, Cécile Lecoeur¹³, Yun Li¹⁰, Valeriya Lyssenko¹⁰², Robert Mahley¹⁰³, Massimo Mangino⁹, Alisa KManning¹, María Teresa Martínez-Larrad³⁹, Jarred B McAteer^6,104,105, Laura J McCulloch⁴, Ruth McPherson¹⁰⁶, Christa Meisinger²¹, David Melzer²⁸, David Meyre¹³, Braxton DMitchell⁴⁵, Mario A Morken⁴⁷, Sutapa Mukherjee^66,83, Silvia Naitza⁶⁵, Narisu Narisu⁴⁷, Matthew J Neville^4,107, Ben A Oostra¹⁰⁸, Marco Orrù⁶⁵, Ruth Pakyz⁴⁵, Colin NA Palmer¹⁰⁹, Giuseppe Paolisso¹¹⁰, Cristian Pattaro⁸², Daniel Pearson⁴⁷, John F Peden^5,27, Nancy LPedersen⁴², Markus Perola^96,111,112, Andreas F H Pfeiffer^67,68, Irene Pichler⁸², Ozren Polasek¹¹³, Danielle Posthuma^23,114, Simon CPotter⁸, Anneli Pouta¹¹⁵, Michael A Province⁴⁴, Bruce MPsaty^116,117, Wolfgang Rathmann¹¹⁸, Nigel WRayner^4,5, Kenneth Rice¹¹⁹, Samuli Ripatti^96,111, Fernando Rivadeneira^22,120, Michael Roden^81,121, Olov Rolandsson¹²², Annelli Sandbaek¹²³, Manjinder Sandhu^3,124, Serena Sanna⁶⁵, Avan Aihie Sayer¹²⁵, Paul Scheet¹²⁶, Laura J Scott¹⁰, Udo Seedorf¹²⁷, Stephen J Sharp³, Beverley Shields⁹⁸, Gunnar Sigurdsson^55,56, Eric J GSijbrands^22,120, Angela Silveira¹²⁸, Laila Simpson^64,66, Andrew Singleton¹²⁹, Nicholas LSmith^130,131, Ulla Sovio¹⁷, Amy Swift⁴⁷, Holly Syddall¹²⁵, Ann-Christine Syvänen¹³², Toshiko Tanaka^133,134, Barbara Thorand²¹, Jean Tichet¹³⁵, Anke Tönjes^60,136, Tiinamaija Tuomi^87,137, André GUitterlinden^22,120, Ko Willems van Dijk^70,138, Mandy van Hoek¹²⁰, Dhiraj Varma⁸, Sophie Visvikis-Siest¹³⁹, Veronique Vitart²⁵, Nicole Vogelzangs¹⁴⁰, Gérard Waeber¹⁴¹, Peter J Wagner^96,111, Andrew Walley¹⁴², GBragi Walters¹⁹, Kim LWard^64,66, Hugh Watkins^5,27, Michael NWeedon²⁸, Sarah H Wild²⁴, Gonneke Willemsen²³, Jaqueline CMWitteman²², John WGYarnell¹⁴³, Eleftheria Zeggini^5,8, Diana Zelenika⁷⁹, Björn Zethelius^43,144, Guangju Zhai⁹, Jing Hua Zhao³, MCarola Zillikens¹²⁰, DIAGRAMConsortium¹⁴⁵, GIANTConsortium¹⁴⁵, Global BPgen Consortium¹⁴⁵,Ingrid B Borecki⁴⁴, Ruth J F Loos³, Pierre Meneton⁸⁰, Patrik KEMagnusson⁴², David MNathan^104,105, Gordon H Williams^69,105, Andrew THattersley⁹⁸, Kaisa Silander^96,111, Veikko Salomaa¹⁴⁶, George Davey Smith³⁸, Stefan R Bornstein⁷³, Peter Schwarz⁷³, Joachim Spranger^67,68, Fredrik Karpe^4,107, Alan R Shuldiner⁴⁵, Cyrus Cooper¹²⁵, George V Dedoussis³⁴, Manuel Serrano-Ríos³⁹, Andrew DMorris¹⁰⁹, Lars Lind¹³², Lyle J Palmer^64,66,84, Frank B Hu1^47,148, Paul WFranks¹⁴⁹, Shah Ebrahim¹⁵⁰, Michael Marmot³⁶, WH Linda Kao^33,151,152, James SPankow¹⁵³, Michael J Sampson¹⁵⁴, Johanna Kuusisto¹⁵⁵, Markku Laakso¹⁵⁵, Torben Hansen^31,156, Oluf Pedersen^31,59,157, Peter Paul Pramstaller^82,158,159, H Erich Wichmann^21,160,161, Thomas Illig²¹, Igor Rudan^24,162,163, Alan F Wright²⁵, Michael Stumvoll⁶⁰, Harry Campbell²⁴, James F Wilson²⁴, Anders Hamsten on behalf of Procardis Consortium¹²⁸, Richard NBergman¹⁶⁴, Thomas A Buchanan^164,165, Francis SCollins⁴⁷, Karen LMohlke¹⁶⁶, Jaakko Tuomilehto^{94,167, 168}, Timo TValle¹⁶⁷, David Altshuler^6,7,104,105, Jerome I Rotter⁶², David SSiscovick¹⁶⁹, Brenda WJ H Penninx¹⁴⁰, Dorret I Boomsma²³, Panos Deloukas⁸, Timothy DSpector^8,9, Timothy MFrayling²⁸, Luigi Ferrucci¹⁷⁰, Augustine Kong¹⁹, Unnur Thorsteinsdottir^19,171, Kari Stefansson^19,171, Cornelia Mvan Duijn²², Yurii SAulchenko²², Antonio Cao⁶⁵, Angelo Scuteri^172,177, David Schlessinger⁴⁷, Manuela Uda⁶⁵, Aimo Ruokonen¹⁷³, Marjo-Riitta Jarvelin^{17,93, 174}, Dawn MWaterworth²⁶, Peter Vollenweider¹⁴¹, Leena Peltonen^{8,48,96,111,112}, Vincent Mooser²⁶, Goncalo R Abecasis¹⁰, Nicholas J Wareham³, Robert Sladek^40,41, Philippe Froguel^13,142, Richard MWatanabe^164,175, James B Meigs^35,105, Leif Groop¹⁰², Michael Boehnke¹⁰, Mark I McCarthy^4,5,107, Jose CFlorez^6,7,104,105 & Inês Barroso¹¹ for the MAGIC investigators

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

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

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

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

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

6 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

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

8 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

9 Twin Research and Genetic Epidemiology Department, King's College London, St Thomas' Hospital Campus, London, UK.

10 Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

11 Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

12 Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.

13 Centre National de la Recherche Scientifique–Unité Mixte de Recherche 8090 , Pasteur Institute, Lille 2 –Droit et Santé University, Lille, France.

14 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

15 University Institute of Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.

16 Swiss Institute of Bioinformatics, Lausanne, Switzerland.

17 Department of Epidemiology and Public Health, Imperial College London, Faculty of Medicine, Norfolk Place, London, UK.

18 Boston University Data Coordinating Center, Boston, Massachusetts, USA.

19 deCODE Genetics, Reykjavik, Iceland.

20 Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

21 Institute of Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.

22 Department of Epidemiology, Erasmus Medical College, Rotterdam, The Netherlands.

23 Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.

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

25 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK.

26 Division of Genetics, Research and Development, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

27 Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

28 Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

29 National Institute of Aging, Baltimore, Maryland, USA.

30 Unit for Child and Adolescent Health and Welfare, National Institute for Health and Welfare, Biocenter Oulu, University of Oulu, Oulu, Finland.

31 Hagedorn Research Institute, Gentofte, Denmark.

32 Department of Medicine and Therapeutics, Level 7, Ninewells Hospital and Medical School, Dundee, UK.

33 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

34 Department of Nutrition–Dietetics, Harokopio University, Athens, Greece.

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

36 Department of Epidemiology and Public Health, University College London, London, UK.

37 Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

38 MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK.

39 Fundación para la Investigación Biomédica del Hospital Clínico San Carlos, Madrid, Spain.

40 Departments of Medicine and Human Genetics, McGill University, Montreal, Canada.

41 Genome Quebec Innovation Centre, Montreal, Canada.

42 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

43 Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

44 Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

45 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.

46 INSERM U 859 , Universite de Lille-Nord de France, Lille, France.

47 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.

48 The Broad Institute, Cambridge, Massachusetts, USA.

49 Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.

50 INSERM U 780 , Paris Sud University, Villejuif, France.

51 The Heart Research Institute, Sydney, New South Wales, Australia.

52 PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands West Australia, Australia.

53 School of Surgery and Pathology, University of Western Australia, Nedlands West Australia, Australia.

54 Department of Social Medicine, University of Bristol, Bristol, UK.

55 Landspitali University Hospital, Reykjavik, Iceland.

56 Icelandic Heart Association, Kopavogur, Iceland.

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

58 Steno Diabetes Center, Gentofte, Denmark.

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

60 Department of Medicine, University of Leipzig, Leipzig, Germany.

61 Endocrinology–Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, France.

62 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

63 Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK.

64 Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Perth, Australia.

65 Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.

66 Western Australian Sleep Disorders Research Institute, Queen Elizabeth Medical Centre II, Perth, Australia.

67 Department of Endocrinology, Diabetes and Nutrition, Charite-Universitaetsmedizin Berlin, Berlin, Germany.

68 Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

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

70 Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

71 Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy.

72 Institut National de la Santé et de la Recherche Médicale, Institut National de la Recherche Agronomique, Université Paris

13 , Bobigny Cedex, France.

73 Department of Medicine III, Division Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.

74 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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

76 Centre Hospitalier Universitaire, de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0802, INSERM U927, Université de Poitiers, Unité de Formation et de Recherche, Médecine Pharmacie, Poitiers, France.

77 Department of Public Health and Clinical Medicine, Section for Nutritional Research, Umeå University, Umeå, Sweden.

78 Department of Clinical Sciences, Obstetrics and Gynecology, University of Oulu, University of Oulu, Finland.

79 Centre National de Génotypage/Institut de génomique/Commissariat à l'énergie atomique, Evry Cedex, France. 80 INSERM U872, Faculté de Médecine Paris Descartes, Paris Cedex, France.

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

82 Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso, Bolzano, Italy, Affiliated Institute of the University Lübeck, Lübeck, Germany.

83 Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Perth, Australia.

84 Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia.

85 Heart Institute of Western Australia, Sir Charles Gairdner Hospital, Nedlands West Australia, Australia.

86 School of Medicine and Pharmacology, University of Western Australia, Nedlands West Australia, Australia.

87 Folkhalsan Research Centre, Helsinki, Finland.

88 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland.

89 Nuffield Department of Surgery, University of Oxford, Oxford, UK.

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

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

92 National Institute for Health and Welfare, Unit of Population Studies, Turku, Finland.

93 Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.

94 Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

95 National Institute for Health and Welfare, Unit for Child and Adolescent Mental Health, Helsinki, Finland.

96 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

97 Department of Internal Medicine and Biocenter Oulu, Oulu, Finland.

98 Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

99 National Institute for Health and Welfare, Unit of Living Conditions, Health and Wellbeing, Helsinki, Finland.

100 Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.

101 The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

102 Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.

103 Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA.

104 Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

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

106 Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

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

108 Department of Clinical Genetics, Erasmus Medical College, Rotterdam, The Netherlands.

109 Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.

110 Department of Geriatric Medicine and Metabolic Disease, Second University of Naples, Naples, Italy.

111 National Institute for Health and Welfare, Unit of Public Health Genomics, Helsinki, Finland.

112 Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

113 Department of Medical Statistics, Epidemiology and Medical Informatics, Andrija Stampar School of Public Health, Medical School, University of Zagreb, Rockefellerova, Zagreb, Croatia.

114 Department of Clinical Genetics, VU University and Medical Center, Amsterdam, The Netherlands.

115 Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland.

116 Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, USA.

117 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

118 Institute of Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

119 Department of Biostatistics, University of Washington, Seattle, Washington, USA.

120 Department of Internal Medicine, Erasmus Medical College, Rotterdam, The Netherlands.

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

122 Department of Public Health and Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.

123 School of Public Health, Department of General Practice, University of Aarhus, Aarhus, Denmark.

124 Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

125 MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK.

126 Department of Epidemiology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.

127 Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany.

128 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

129 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

130 Department of Epidemiology, University of Washington, Seattle, Washington, USA.

131 Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

132 Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

133 Medstar Research Institute, Baltimore, Maryland, USA.

134 Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

135 Institut interrégional pour la santé (IRSA), La Riche, France.

136 Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany.

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

138 Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands.

139 Research Unit, Cardiovascular Genetics, Nancy University Henri Poincaré, Nancy, France.

140 EMGO Institute for Health and Care Research, Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.

141 Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

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

143 Epidemiology and Public Health, Queen's University Belfast, Belfast, UK.

144 Medical Products Agency, Uppsala, Sweden.

145 See Supplementary Note for a full list of authors.

146 National Institute for Health and Welfare, Unit of Chronic Disease Epidemiology and Prevention, Helsinki, Finland.

147 Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

148 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

149 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden.

150 London School of Hygiene and Tropical Medicine, London, UK.

151 Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

152 The Welch Center for Prevention, Epidemiology, and Clinical Research, School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

153 Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

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

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

156 Faculty of Health Science, University of Southern Denmark, Odense, Denmark.

157 Institute of Biomedical Science, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

158 Department of Neurology, General Central Hospital, Bolzano, Italy.

159 Department of Neurology, University of Lübeck, Lübeck, Germany.

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

161 Klinikum Grosshadern, Munich, Germany.

162 School of Medicine, University of Split, Split, Croatia.

163 Gen-Info Ltd., Zagreb, Croatia.

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

165 Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

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

167 National Institute for Health and Welfare, Unit of Diabetes Prevention, Helsinki, Finland.

168 South Ostrobothnia Central Hospital, Seinajoki, Finland.

169 Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA.

170 Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.

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

172 Lab of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

173 Department of Clinical Sciences/Clinical Chemistry, University of Oulu, University of Oulu, Oulu, Finland.

174 National Institute of Health and Welfare, Oulu, Finland.

175 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

176 MRC–Health Protection Agency Centre for Environment and Health, Imperial College London, London, UK.

177 UOC Geriatria, Istituto Nazionale Ricovero e cura per Anziani (INRCA) IRCCS, Rome, Italy.

178 These authors contributed equally to this work. Correspondence should be addressed to M.B. (boehnke@umich.edu), M.I.M. (mark.mccarthy@drl.ox.ac.uk), J.C.F. (jcflorez@partners.org) or I.B. (ib1 @sanger.ac.uk).

GLGC Consortium:

Tanya M. Teslovich,^{1, 118} , Kiran Musunuru,^{2, 3, 4, 5, 6, 118} , Albert V. Smith,^{7, 8} , Andrew C. Edmondson,^{9, 10} , Ioannis M. Stylianou,¹⁰ , Masahiro Koseki,¹¹ , James P. Pirruccello,^{2, 5, 6} , Samuli Ripatti,^{12, 13} , Daniel I. Chasman,^{4, 14} , Cristen J. Willer,¹ , Christopher T. Johansen,¹⁵ , Sigrid W. Fouchier,¹⁶ , Aaron Isaacs,¹⁷ , Gina M. Peloso,^{18, 19} , Maja Barbalic,²⁰ , Sally L. Ricketts,²¹ , Joshua C. Bis,²² , Yurii S. Aulchenko,¹⁷ , Gudmar Thorleifsson,²³ , Mary F. Feitosa,²⁴ , John Chambers,²⁵ , Marju Orho-Melander,²⁶ , Olle Melander,²⁶ , Toby Johnson,²⁷ , Xiaohui Li,²⁸ , Xiuqing Guo,²⁸ , Mingyao Li,^{9, 10} , Yoon Shin Cho,²⁹ , Min Jin Go,²⁹ , Young Jin Kim,²⁹ , Jong-Young Lee,²⁹ , Taesung Park,^{30, 31} , Kyunga Kim,³² , Xueling Sim,³³ , Rick Twee-Hee Ong,³⁴ , Damien C. Croteau-Chonka,³⁵ , Leslie A. Lange,³⁵ , Joshua D. Smith,³⁶ , Kijoung Song,³⁷ , Jing Hua Zhao,³⁸ , Xin Yuan,³⁷ , Jian'an Luan,³⁸ , Claudia Lamina,³⁹ , Andreas Ziegler,⁴⁰ , Weihua Zhang,²⁵ , Robert Y. L. Zee,^{4, 14} , Alan F. Wright,⁴¹ , Jacqueline C. M. Witteman,^{17, 42} , James F. Wilson,⁴³ , Gonneke Willemsen,⁴⁴ , H.-Erich Wichmann,⁴⁵ , John B. Whitfield,⁴⁶ , Dawn M. Waterworth,³⁷ , Nicholas J. Wareham,³⁸ , Gérard Waeber,⁴⁷ , Peter Vollenweider,⁴⁷ , Benjamin F. Voight,^{2, 5} , Veronique Vitart,⁴¹ , Andre G. Uitterlinden,^{17, 42, 48} , Manuela Uda,⁴⁹ , Jaakko Tuomilehto,⁵⁰ , John R. Thompson,⁵¹ , Toshiko Tanaka,^{52, 53} , Ida Surakka,^{12, 13} , Heather M. Stringham,¹ , Tim D. Spector,⁵⁴ , Nicole Soranzo,^{54, 55} , Johannes H. Smit,⁵⁶ , Juha Sinisalo,⁵⁷ , Kaisa Silander,^{12, 13} , Eric J. G. Sijbrands,^{17, 48} , Angelo Scuteri,⁵⁸ , James Scott,⁵⁹ , David Schlessinger,⁶⁰ , Serena Sanna,⁴⁹ , Veikko Salomaa,⁵⁰ , Juha Saharinen,¹² , Chiara Sabatti,⁶¹ , Aimo Ruokonen,⁶² , Igor Rudan,⁴³ , Lynda M. Rose,¹⁴ , Robert Roberts,⁶³ , Mark Rieder,³⁶ , Bruce M. Psaty,⁶⁴ , Peter P. Pramstaller,⁶⁵ , Irene Pichler,⁶⁵ , Markus Perola,^{12, 13} , Brenda W. J. H. Penninx,⁵⁶ , Nancy L. Pedersen,⁶⁶ , Cristian Pattaro,⁶⁵ , Alex N. Parker,⁶⁷ , Guillaume Pare,⁶⁸ , Ben A. Oostra,⁶⁹ , Christopher J. O'Donnell,^{4, 19} , Markku S. Nieminen,⁵⁷ , Deborah A. Nickerson,³⁶ , Grant W. Montgomery,⁴⁶ , Thomas Meitinger,^{70, 71} , Ruth McPherson,⁶³ , Mark I. McCarthy,^{72, 73, 74} , Wendy McArdle,⁷⁵ , David Masson,¹¹ , Nicholas G. Martin,⁴⁶ , Fabio Marroni,⁷⁶ , Massimo Mangino,⁵⁴ , Patrik K. E. Magnusson,⁶⁶ , Gavin Lucas,⁷⁷ , Robert Luben,²¹ , Ruth J. F. Loos,³⁸ , Marja-Liisa Lokki,⁷⁸ , Guillaume Lettre,⁷⁹ , Claudia Langenberg,³⁸ , Lenore J. Launer,⁸⁰ , Edward G. Lakatta,⁶⁰ , Reijo Laaksonen,⁸¹ , Kirsten O. Kyvik,⁸² , Florian Kronenberg,³⁹ , Inke R. König,⁴⁰ , Kay-Tee Khaw,²¹ , Jaakko Kaprio,^{12, 13, 83} , Lee M. Kaplan,⁸⁴ , Åsa Johansson,⁸⁵ , Marjo-Riitta Jarvelin,^{86, 87} , A. Cecile J. W. Janssens,¹⁷ , Erik Ingelsson,⁶⁶ , Wilmar Igl,⁸⁵ , G. Kees Hovingh,¹⁶ , Jouke-Jan Hottenga,⁴⁴ , Albert Hofman,^{17, 42} , Andrew A. Hicks,⁶⁵ , Christian Hengstenberg,⁸⁸ , Iris M. Heid,^{45, 89} , Caroline Hayward,⁴¹ , Aki S. Havulinna,^{50, 90} , Nicholas D. Hastie,⁴¹ , Tamara B. Harris,⁸⁰ , Talin Haritunians,²⁸ , Alistair S. Hall,⁹¹ , Ulf Gyllensten,⁸⁵ , Candace Guiducci,⁵ , Leif C. Groop,^{26, 92} , Elena Gonzalez,⁵ , Christian Gieger,⁴⁵ , Nelson B. Freimer,⁹³ , Luigi Ferrucci,⁹⁴ , Jeanette Erdmann,⁹⁵ , Paul Elliott,^{86, 96} , Kenechi G. Ejebe,⁵ , Angela Döring,⁴⁵ , Anna F. Dominiczak,⁹⁷ , Serkalem Demissie,^{18, 19} , Panagiotis Deloukas,⁵⁵ , Eco J. C. de Geus,⁴⁴ , Ulf de Faire,⁹⁸ , Gabriel Crawford,⁵ , Francis S. Collins,⁹⁹ , Yii-der I. Chen,²⁸ , Mark J. Caulfield,²⁷ , Harry Campbell,⁴³ , Noel P. Burtt,⁵ , Lori L. Bonnycastle,⁹⁹ , Dorret I. Boomsma,⁴⁴ , S. Matthijs Boekholdt,¹⁰⁰ , Richard N. Bergman,¹⁰¹ , Inês Barroso,⁵⁵ , Stefania Bandinelli,¹⁰² , Christie M. Ballantyne,¹⁰³ , Themistocles L. Assimes,¹⁰⁴ , Thomas Quertermous,¹⁰⁴ , David Altshuler,^{2, 4, 5} , Mark Seielstad,³⁴ , Tien Y. Wong,¹⁰⁵ , E-Shyong Tai,¹⁰⁶ , Alan B. Feranil,¹⁰⁷ , Christopher W. Kuzawa,¹⁰⁸ , Linda S. Adair,¹⁰⁹ , Herman A. Taylor Jr,¹¹⁰ , Ingrid B. Borecki,²⁴ , Stacey B. Gabriel,⁵ , James G. Wilson,¹¹⁰ , Hilma Holm,²³ , Unnur Thorsteinsdottir,^{8, 23} , Vilmundur Gudnason,^{7, 8} , Ronald M. Krauss,¹¹¹ , Karen L. Mohlke,³⁵ , Jose M. Ordovas,^{112, 113} , Patricia B. Munroe,¹¹⁴ , Jaspal S. Kooner,⁵⁹ , Alan R. Tall,¹¹ , Robert A. Hegele,¹⁵ , John J.P. Kastelein,¹⁶ , Eric E. Schadt,¹¹⁵ , Jerome I. Rotter,²⁸ , Eric Boerwinkle,²⁰ , David P. Strachan,¹¹⁶ , Vincent Mooser,³⁷ , Kari Stefansson,^{8, 23} , Muredach P. Reilly,^{9, 10} , Nilesh J Samani,¹¹⁷ , Heribert Schunkert,⁹⁵ , L. Adrienne Cupples,^{18, 19, 118} , Manjinder S. Sandhu,^{21, 38, 55, 118} , Paul M Ridker,^{4, 14, 118} , Daniel J. Rader,^{9, 10, 118} , Cornelia M. van Duijn,^{17, 42, 118} , Leena Peltonen,¹¹⁹ , Gonçalo R. Abecasis,^{1, 118} , Michael Boehnke^{1, 118} , & Sekar Kathiresan,

1 Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

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

3 Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

4 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

5 Broad Institute, Cambridge, Massachusetts 02142, USA.

6 Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

7 Icelandic Heart Association, Heart Preventive Clinic and Research Institute, 201 Kopavogur, Iceland.

8 University of Iceland, 101 Reykjavik, Iceland.

9 Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

10 Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.

11 Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.

12 Institute for Molecular Medicine Finland FIMM, University of Helsinki, FI-00014 Helsinki, Finland.

13 National Institute for Health and Welfare, P.O. Box 104, FI-00251 Helsinki, Finland.

14 Division of Preventive Medicine, Brigham and Women's Hospital, Boston Massachusetts 02215, USA.

15 Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.

16 Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

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

18 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.

19 National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts 01702, USA.

20 Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

21 Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.

22 Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington 98101, USA.

23 deCODE Genetics, 101 Reykjavik, Iceland.

24 Division of Statistical Genomics in the Center for Genome Sciences, Washington University School of Medicine, St Louis, Missouri 63108, USA.

25 Department of Epidemiology and Public Health, Imperial College London, London W2 1PG, UK.

26 Department of Clinical Sciences, Lund University, SE-20502, Malmö, Sweden.

27 Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.

28 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

29 Center for Genome Science, National Institute of Health, Seoul 122-701, Republic of Korea.

30 Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.

31 Department of Statistics, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.

32 Department of Statistics, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

33 Centre for Molecular Epidemiology, National University of Singapore, Singapore, 117597, Republic of Singapore.

34 Genome Institute of Singapore, Singapore 138672, Republic of Singapore.

35 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

36 Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

37 Genetics Division, GlaxoSmithKline R&D, King of Prussia, Pennsylvania 19406, USA.

38 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

39 Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstrasse 41, A-6020 Innsbruck, Austria.

40 Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, 23562 Lübeck, Germany.

41 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.

42 Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA) and Center of Medical Systems Biology (CMSB), 2300 RC Leiden, The Netherlands.

43 Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.

44 Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands.

45 Institute of Epidemiology, Helmholtz Zentrum Munchen – German Research Center for Environmental Health, 85764 Neuherberg, Germany.

46 Genetic Epidemiology Unit, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland 4029, Australia.

47 Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.

48 Department of Internal Medicine, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

49 Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.

50 Department of Chronic Disease Prevention, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.

51 Department of Health Sciences, University of Leicester, Leicester LE1 6TP, UK.

52 Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.

53 Medstar Research Institute, Baltimore, Maryland 21218, USA.

54 Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.

55 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

56 Department of Psychiatry, EMGO Institute, Neuroscience Campus Amsterdam, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.

57 Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), FI-00029 Helsinki, Finland.

58 Unita Operativa Geriatria, Istituto Nazionale Ricovero e Cura Anziani (INRCA), Istituto Ricovero e Cura a Carattere Scientifico (IRCCS), Via Cassia 1167, 00189 Rome, Italy.

59 Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.

60 Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.

61 Department of Health Research and Policy, Stanford University, Stanford, California 94305, USA.

62 Department of Clinical Chemistry, University of Oulu, FI-90220 Oulu, Finland.

63 The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa, Ottawa K1Y 4W7, Canada.

64 Departments of Medicine, Epidemiology, and Health Services, University of Washington, Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.

65 Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso 1, 39100 Bolzano, Italy – affiliated institute of the University of Lübeck, Germany.

66 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden.

67 Amgen, Thousand Oaks, California 91320, USA.

68 Genetic and Molecular Epidemiology Laboratory, McMaster University, Hamilton, Ontario L8N3Z5, Canada.

69 Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.

70 Institut fur Humangenetik, Helmholtz Zentrum Munchen, Deutsches Forschungszentrum fur Umwelt und Gesundheit, 85764 Neuherberg, Germany.

71 Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675 Muenchen, Germany.

72 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

73 Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

74 Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.

75 Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol BS8 2BN, UK.

76 Institute of Applied Genomics, via Linussio 51, 33100 Udine, Italy.

77 Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigacio Medica, 08003 Barcelona, Spain.

78 Transplantation Laboratory, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland.

79 Montreal Heart Institute (Research Center), Université de Montréal, Montréal, Québec H1T 1C8, Canada.

80 Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

81 Science Center, Tampere University Hospital, FI-33521 Tampere, Finland.

82 Institute of Regional Health Research and the Danish Twin Registry, Institute of Public Health, University of Southern Denmark, JBWinsløws Vej 9B, DK-5000, Odense, Denmark.

83 Faculty of Medicine, Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland.

84 Massachusetts General Hospital Weight Center, Boston, Massachusetts 02114, USA.

85 Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, SE-75185 Uppsala, Sweden.

86 Department of Epidemiology & Biostatistics, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK.

87 Department of Public Health Science and General Practice, University of Oulu, FI-90220 Oulu, Finland.

88 Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany.

89 Department of Epidemiology and Preventive Medicine Regensburg University Medical Center Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.

90 Department of Biomedical Engineering and Computational Science, Aalto University School of Science and Technology, FI-00076 Aalto, Finland.

91 LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.

92 Department of Medicine, Helsinki University Hospital, FI-00029 Helsinki, Finland.

93 Department of Psychiatry, Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.

94 Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21225, USA.

95 Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany.

96 MRC-HPA Centre for Environment and Health, Imperial College London, London W2 1PG, UK.

97 BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.

98 Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.

99 National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.

100 Departments of Vascular Medicine & Cardiology, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands.

101 Department of Physiology and Biophysics, University of Southern California, Los Angeles, California 90033, USA.

102 Geriatric Unit, Azienda Sanitaria Firenze (ASF), 50125 Florence, Italy.

103 Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.

104 Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

105 Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Republic of Singapore.

106 Departments of Medicine/Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.

107 Office of Population Studies Foundation, University of San Carlos, Cebu City 6000, Philippines.

108 Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.

109 Department of Nutrition, Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina 27516, USA.

110 Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39126, USA.

111 Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.

112 Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.

113 Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.

114 Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

115 Sage Bionetworks, Seattle, Washington 98109, USA.

116 Division of Community Health Sciences, St George's University of London, London SW17 0RE, UK.

117 Department of Cardiovascular Sciences, University of Leicester, NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK.