A genome-wide association study identifies novel risk loci for type 2 diabetes


Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case–control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing β-cells, and two linkage disequilibrium blocks that contain genes potentially involved in β-cell development or function (IDE–KIF11–HHEX and EXT2–ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.

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Figure 1: Graphical summary of stage 1 association results.
Figure 2: Pairwise linkage disequilibrium diagrams for four novel T2DM-associated loci.


  1. 1

    Permutt, M. A., Wasson, J. & Cox, N. Genetic epidemiology of diabetes. J. Clin. Invest. 115, 1431–1439 (2005)

    CAS  Article  Google Scholar 

  2. 2

    Horikawa, Y. et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet. 26, 163–175 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Meyre, D. et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nature Genet. 37, 863–867 (2005)

    CAS  Article  Google Scholar 

  4. 4

    Love-Gregory, L. D. et al. A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4α gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an ashkenazi jewish population. Diabetes 53, 1134–1140 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Silander, K. et al. Genetic variation near the hepatocyte nuclear factor-4α gene predicts susceptibility to type 2 diabetes. Diabetes 53, 1141–1149 (2004)

    CAS  Article  Google Scholar 

  6. 6

    Vasseur, F. et al. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum. Mol. Genet. 11, 2607–2614 (2002)

    CAS  Article  Google Scholar 

  7. 7

    Altshuler, D. et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet. 26, 76–80 (2000)

    CAS  Article  Google Scholar 

  8. 8

    Gloyn, A. L. et al. Large-scale association studies of variants in genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52, 568–572 (2003)

    CAS  Article  Google Scholar 

  9. 9

    Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320–323 (2006)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Zhang, C. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men. Diabetes 55, 2645–2648 (2006)

    CAS  Article  Google Scholar 

  11. 11

    Damcott, C. M. et al. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes 55, 2654–2659 (2006)

    CAS  Article  Google Scholar 

  12. 12

    Scott, L. J. et al. Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes 55, 2649–2653 (2006)

    CAS  Article  Google Scholar 

  13. 13

    Groves, C. J. et al. Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes 55, 2640–2644 (2006)

    CAS  Article  Google Scholar 

  14. 14

    Cauchi, S. et al. TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 55, 3189–3192 (2006)

    CAS  Article  Google Scholar 

  15. 15

    Chandak, G. R. et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 50, 63–67 (2007)

    CAS  Article  Google Scholar 

  16. 16

    Florez, J. C. et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N. Engl. J. Med. 355, 241–250 (2006)

    CAS  Article  Google Scholar 

  17. 17

    Humphries, S. E. et al. Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European whites, Indian Asians and Afro-Caribbean men and women. J. Mol. Med. 84, 1–10 (2006)

    Article  Google Scholar 

  18. 18

    Parton, L. E. et al. Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis. Am. J. Physiol. Endocrinol. Metab. 291, E982–E994 (2006)

    CAS  Article  Google Scholar 

  19. 19

    Saxena, R. et al. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55, 2890–2895 (2006)

    CAS  Article  Google Scholar 

  20. 20

    Weedon, M. N. et al. Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med. 3, e374 (2006)

    Article  Google Scholar 

  21. 21

    Fingerlin, T. E., Boehnke, M. & Abecasis, G. R. Increasing the power and efficiency of disease-marker case-control association studies through use of allele-sharing information. Am. J. Hum. Genet. 74, 432–443 (2004)

    CAS  Article  Google Scholar 

  22. 22

    Balkau, B. An epidemiologic survey from a network of French Health Examination Centres, (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome. Rev. Epidemiol. Sante Publique 44, 373–375 (1996)

    CAS  PubMed  Google Scholar 

  23. 23

    International HapMap Consortium A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

    ADS  Article  Google Scholar 

  24. 24

    Campbell, C. D. et al. Demonstrating stratification in a European American population. Nature Genet. 37, 868–872 (2005)

    CAS  Article  Google Scholar 

  25. 25

    Chimienti, F. et al. In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J. Cell Sci. 119, 4199–4206 (2006)

    CAS  Article  Google Scholar 

  26. 26

    Duggirala, R. et al. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am. J. Hum. Genet. 64, 1127–1140 (1999)

    CAS  Article  Google Scholar 

  27. 27

    Ghosh, S. et al. The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes. Am. J. Hum. Genet. 67, 1174–1185 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Meigs, J. B., Panhuysen, C. I., Myers, R. H., Wilson, P. W. & Cupples, L. A. A genome-wide scan for loci linked to plasma levels of glucose and HbA(1c) in a community-based sample of Caucasian pedigrees: The Framingham Offspring Study. Diabetes 51, 833–840 (2002)

    CAS  Article  Google Scholar 

  29. 29

    Wiltshire, S. et al. A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am. J. Hum. Genet. 69, 553–569 (2001)

    CAS  Article  Google Scholar 

  30. 30

    Bort, R., Martinez-Barbera, J. P., Beddington, R. S. & Zaret, K. S. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 131, 797–806 (2004)

    CAS  Article  Google Scholar 

  31. 31

    Bort, R., Signore, M., Tremblay, K., Martinez Barbera, J. P. & Zaret, K. S. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev. Biol. 290, 44–56 (2006)

    CAS  Article  Google Scholar 

  32. 32

    Foley, A. C. & Mercola, M. Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes Dev. 19, 387–396 (2005)

    CAS  Article  Google Scholar 

  33. 33

    Bennett, R. G., Hamel, F. G. & Duckworth, W. C. An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures. Diabetes 52, 2315–2320 (2003)

    CAS  Article  Google Scholar 

  34. 34

    Farris, W. et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc. Natl Acad. Sci. USA 100, 4162–4167 (2003)

    ADS  CAS  Article  Google Scholar 

  35. 35

    Groves, C. J. et al. Association and haplotype analysis of the insulin-degrading enzyme (IDE) gene, a strong positional and biological candidate for type 2 diabetes susceptibility. Diabetes 52, 1300–1305 (2003)

    CAS  Article  Google Scholar 

  36. 36

    Karamohamed, S. et al. Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study. Diabetes 52, 1562–1567 (2003)

    CAS  Article  Google Scholar 

  37. 37

    Florez, J. C. et al. High-density haplotype structure and association testing of the insulin-degrading enzyme (IDE) gene with type 2 diabetes in 4,206 people. Diabetes 55, 128–135 (2006)

    CAS  Article  Google Scholar 

  38. 38

    Apelqvist, A., Ahlgren, U. & Edlund, H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr. Biol. 7, 801–804 (1997)

    CAS  Article  Google Scholar 

  39. 39

    Thomas, M. K., Rastalsky, N., Lee, J. H. & Habener, J. F. Hedgehog signaling regulation of insulin production by pancreatic β-cells. Diabetes 49, 2039–2047 (2000)

    CAS  Article  Google Scholar 

  40. 40

    Boras-Granic, K., Grosschedl, R. & Hamel, P. A. Genetic interaction between Lef1 and Alx4 is required for early embryonic development. Int. J. Dev. Biol. 50, 601–610 (2006)

    Article  Google Scholar 

  41. 41

    Di Rienzo, A. & Hudson, R. R. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet. 21, 596–601 (2005)

    CAS  Article  Google Scholar 

  42. 42

    Pritchard, J. K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001)

    CAS  Article  Google Scholar 

  43. 43

    Hallaq, H. et al. A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels. Development 131, 5197–5209 (2004)

    CAS  Article  Google Scholar 

  44. 44

    Stickens, D. et al. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet. 14, 25–32 (1996)

    CAS  Article  Google Scholar 

  45. 45

    Pritchard, J. K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Sasieni, P. D. From genotypes to genes: doubling the sample size. Biometrics 53, 1253–1261 (1997)

    MathSciNet  CAS  Article  Google Scholar 

  47. 47

    Clayton, D. G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nature Genet. 37, 1243–1246 (2005)

    CAS  Article  Google Scholar 

  48. 48

    Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999)

    CAS  Article  Google Scholar 

  49. 49

    Reich, D. E. & Goldstein, D. B. Detecting association in a case-control study while correcting for population stratification. Genet. Epidemiol. 20, 4–16 (2001)

    CAS  Article  Google Scholar 

  50. 50

    Kohler, K. & Bickeboller, H. Case-control association tests correcting for population stratification. Ann. Hum. Genet. 70, 98–115 (2006)

    CAS  Article  Google Scholar 

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This work was funded by Genome Canada, Génome Québec, and the Canada Foundation for Innovation. Cohort recruitment was supported by the Association Française des Diabétiques, INSERM, CNAMTS, Centre Hospitalier Universitaire Poitiers, La Fondation de France and industrial partners. We thank all individuals who participated as cases or controls in this study. C. Petit, J-P. Riveline and S. Franc were instrumental in recruitment and S. Brunet, F. Bacot, R. Frechette, V. Catudal, M. Deweirder, F. Allegaert, P. Laflamme, P. Lepage, W. Astle, M. Leboeuf and S. Leroux provided technical assistance. K. Shazand and N. Foisset provided organizational guidance. Large-scale computations were made possible by the CLUMEQ supercomputer facility.

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Correspondence to Constantin Polychronakos.

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Sladek, R., Rocheleau, G., Rung, J. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007). https://doi.org/10.1038/nature05616

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