Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes


Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10−6). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 × 10−8) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Genome-wide plots of −log10 P values from stratified 1-d.f.


  1. Bell, G.I., Horita, S. & Karam, J.H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33, 176–183 (1984).

    CAS  Article  Google Scholar 

  2. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

    CAS  Article  Google Scholar 

  3. Nistico, L. et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum. Mol. Genet. 5, 1075–1080 (1996).

    CAS  Article  Google Scholar 

  4. Lowe, C.E. et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat. Genet. 39, 1074–1082 (2007).

    CAS  Article  Google Scholar 

  5. Smyth, D.J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617–619 (2006).

    CAS  Article  Google Scholar 

  6. Concannon, P. et al. A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 57, 2858–2861 (2008).

    CAS  Article  Google Scholar 

  7. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  8. Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007).

    CAS  Article  Google Scholar 

  9. Todd, J.A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).

    CAS  Article  Google Scholar 

  10. Smyth, D.J. et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

    CAS  Article  Google Scholar 

  11. Fung, E. et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun. 10, 188–191 (2009).

    CAS  Article  Google Scholar 

  12. Cooper, J.D. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 40, 1399–1401 (2008).

    CAS  Article  Google Scholar 

  13. Cooper, J.D. et al. Analysis of 55 autoimmune disease and type 2 diabetes loci: further confirmation of chromosomes 4q27, 12q13.2 and 12q24.13 as a type 1 diabetes loci, and support for a new locus in 12q13.3-q14.1. Genes Immun (in the press).

  14. Mueller, P.W. et al. Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. J. Am. Soc. Nephrol. 17, 1782–1790 (2006).

    CAS  Article  Google Scholar 

  15. Baum, A.E. et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol. Psychiatry 13, 197–207 (2008).

    CAS  Article  Google Scholar 

  16. Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887–892 (2007).

    CAS  Article  Google Scholar 

  17. Smyth, D.J. et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes 57, 1730–1737 (2008).

    CAS  Article  Google Scholar 

  18. Bjornvold, M. et al. Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes. Diabetologia 51, 589–596 (2008).

    CAS  Article  Google Scholar 

  19. Senee, V. et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat. Genet. 38, 682–687 (2006).

    CAS  Article  Google Scholar 

  20. Shiow, L.R. et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006).

    CAS  Article  Google Scholar 

  21. Power, C. & Elliott, J. Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 34–41 (2006).

    Article  Google Scholar 

  22. Glumer, C., Jorgensen, T. & Borch-Johnsen, K. Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study. Diabetes Care 26, 2335–2340 (2003).

    Article  Google Scholar 

  23. Teo, Y.Y. et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741–2746 (2007).

    CAS  Article  Google Scholar 

  24. Mantel, N. Chi-square tests with one degree of freedom: extension of the Mantel-Haenszel procedure. J. Am. Stat. Assoc. 58, 690–700 (1963).

    Google Scholar 

  25. Clayton, D. Testing for association on the X chromosome. Biostatistics 9, 593–600 (2008).

    Article  Google Scholar 

  26. Chapman, J.M., Cooper, J.D., Todd, J.A. & Clayton, D.G. Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum. Hered. 56, 18–31 (2003).

    Article  Google Scholar 

  27. Tibshirani, R. Regression shrinkage and selection via the lasso. J. R. Statist. Soc. B. 58, 267–288 (1996).

    Google Scholar 

  28. Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    Article  Google Scholar 

  29. Hakonarson, H. et al. A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes 57, 1143–1146 (2008).

    CAS  Article  Google Scholar 

Download references


This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Further support was provided by a grant from the NIDDK (DK46635) to P.C. and a joint JDRF and Wellcome Trust grant to the Diabetes and Inflammation Laboratory at Cambridge, which also received support from the National Institute for Health Research Cambridge Biomedical Research Centre. D.C. is the recipient of a Wellcome Trust Principal Research Fellowship.

We acknowledge the contributions of the following individuals: J. Alipaz, A. Simpson, J. Brown and J. Garsetti for assistance with project management; M. Hardy and K. Downes for genotyping; M. Maisuria for DNA sample coordination and quality control; J. Hilner and J. Pierce for managing T1DGC Data and DNA resources; J. Allen, N. Ovington, V. Everett, G. Dolman and M. Brown for data services and computing; and L. Smink, O. Burren, J. Mychaleckyj and N. Goodman for bioinformatics support.

We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the Medical Research Council and the Wellcome Trust. We thank The Avon Longitudinal Study of Parents and Children laboratory in Bristol and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton for preparing and providing the control DNA samples. We thank the Human Biological Data Interchange and Diabetes UK for providing DNA samples from USA and UK multiplex families, respectively. Danish subjects were from the Danish Society of Childhood Diabetes (DSBD) and control DNA samples were provided by T. Hansen, O. Pedersen, K. Borch-Johnsen and T. Joergensen. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data are available from

We gratefully acknowledge the Genetics of Kidneys in Diabetes (GoKinD) study for generously allowing the use of their sample SNP allele intensity and genotype data, which was obtained from the Genetic Association Information Network (GAIN) database (dbGAP, phs000018.v1.p1)12.

We gratefully acknowledge the National Institute of Mental Health for generously allowing the use of their control CEL and genotype data. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the “Molecular Genetics of Schizophrenia II” (MGS-2) collaboration. The investigators and coinvestigators are as follows: ENH/Northwestern University, MH059571, P.V. Gejman (collaboration coordinator: PI) and A.R. Sanders; Emory University School of Medicine, MH59587, F. Amin (PI); Louisiana State University Health Sciences Center, MH067257, N. Buccola (PI); University of California-Irvine, MH60870, W. Byerley (PI); Washington University, St. Louis, U01, MH060879, C.R. Cloninger (PI); University of Iowa, MH59566, R. Crowe, (PI) and D. Black; University of Colorado, Denver, MH059565, R. Freedman (PI); University of Pennsylvania, MH061675, D. Levinson (PI); University of Queensland, MH059588, B. Mowry (PI); Mt. Sinai School of Medicine, MH59586, J. Silverman (PI). The samples were collected by V.L. Nimgaonkar's group at the University of Pittsburgh, as part of a multi-institutional collaborative research project with J. Smoller and P. Sklar (Massachusetts General Hospital) (grant MH 63420).

Author information

Authors and Affiliations




J.C.B. and D.G.C. helped design the study, and carried out the statistical analyses. J.C.B., D.G.C. and P.C. drafted the manuscript. P.C. managed the editing of the manuscript. F.P., C.J., J.A.T., B.A., H.A.E., G.M., J.N., C.N., P.C. and S.S.R. (Chair) are members of the T1DGC Steering Committee, and contributed to the general planning and design of the study, and to the writing of the manuscript. F.P. and J.N. also coordinated the inclusion of the Danish case-control samples. N.M.W. and H. Schuilenburg provided data services. J.D.C. and V.P. assisted with data analyses. D.J.S. carried out genotyping, and H. Stevens provided DNA sample coordination and quality control. The T1DGC provided biospecimens and data from families with T1D.

Corresponding author

Correspondence to Patrick Concannon.

Additional information

A full list of members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1–3, Supplementary Note and Supplementary Methods (PDF 377 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Barrett, J., Clayton, D., Concannon, P. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41, 703–707 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing