Current Diabetes Reports

, Volume 9, Issue 2, pp 164–171 | Cite as

Genome-wide association studies in type 2 diabetes

Article

Abstract

Despite numerous candidate gene and linkage studies, the field of type 2 diabetes (T2D) genetics had until recently succeeded in identifying few genuine disease-susceptibility loci. The advent of genomewide association (GWA) scans has transformed the situation, leading to an expansion in the number of established, robustly replicating T2D loci to almost 20. These novel findings offer unique insights into the pathogenesis of T2D and in the main point toward the etiologic importance of disorders of β-cell development and function. All associated variants have common allele frequencies in the discovery populations, and exert modest to small effects on the risk of disease, characteristics that limit their prognostic and diagnostic potential. However, ongoing studies focusing on the role of copy number variation and targeting low-frequency polymorphisms should identify additional T2D susceptibility loci, some of which may have larger effect sizes and offer better individual prediction of disease risk.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Köbberling J, Tillil H: Empirical risk figures for first degree relatives of non-insulin-dependent diabetics. In The Genetics of Diabetes Mellitus. Edited by Köbberling J, Tattersall R. London: Academic Press; 1982:201–209.Google Scholar
  2. 2.
    McCarthy MI: Growing evidence for diabetes susceptibility genes from genome scan data. Curr Diab Rep 2003, 3:159–167.PubMedCrossRefGoogle Scholar
  3. 3.
    Guan W, Pluzhnikov A, Cox NJ, Boehnke M; International Type 2 Diabetes Linkage Analysis Consortium: Meta-analysis of 23 type 2 diabetes linkage studies from the international type 2 diabetes linkage analysis consortium. Hum Hered 2008, 66:35–49.PubMedCrossRefGoogle Scholar
  4. 4.
    International HapMap Consortium: A haplotype map of the human genome. Nature 2005, 437:1299–1320.CrossRefGoogle Scholar
  5. 5.
    Frayling TM, Timpson NJ, Weedon MN, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316:889–894.PubMedCrossRefGoogle Scholar
  6. 6.
    Altshuler D, Hirschhorn JN, Klannemark M, et al.: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000, 26:76–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Gloyn AL, Weedon MN, Owen KR, et al.: Large scale association studies of variants in genes encoding the pancreatic beta-cell K-ATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with increased risk of type 2 Diabetes. Diabetes 2003, 52:568–572.PubMedCrossRefGoogle Scholar
  8. 8.
    Sandhu MS, Weedon MN, Fawcett KA, et al.: Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 2007, 39:951–953.PubMedCrossRefGoogle Scholar
  9. 9.
    Winckler W, Weedon MN, Graham RR, et al.: Evaluation of common variants in the six known MODY genes for association with type 2 Diabetes. Diabetes 2007, 56:685–693.PubMedCrossRefGoogle Scholar
  10. 10.
    Gudmundsson J, Sulem P, Steinthorsdottir V, et al.: Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 2007, 39:977–983.PubMedCrossRefGoogle Scholar
  11. 11.
    Grant SF, Thorleifsson G, Reynisdottir I, et al.: Variant of transcription factor 7-like 2 (TFC7L2) gene confers risk of type 2 diabetes. Nat Genet 2006, 38:320–323.PubMedCrossRefGoogle Scholar
  12. 12.
    Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007, 316:1331–1336.CrossRefGoogle Scholar
  13. 13.
    Scott LJ, Mohlke KL, Bonnycastle LL, et al.: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007, 316:1341–1345.PubMedCrossRefGoogle Scholar
  14. 14.
    Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447:661–678.CrossRefGoogle Scholar
  15. 15.
    Zeggini E, Weedon MN, Lindgren CM, et al.: Replication of genome-wide association signals in U.K. samples reveals risk loci for type 2 diabetes. Science 2007, 316:1336–1341.PubMedCrossRefGoogle Scholar
  16. 16.
    Sladek R, Rocheleau G, Rung J, et al.: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007, 445:828–830.CrossRefGoogle Scholar
  17. 17.
    Salonen JT, Uimari P, Aalto JM, et al.: Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium. Am J Hum Genet 2007, 81:338–345.PubMedCrossRefGoogle Scholar
  18. 18.
    Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al.: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007, 39:770–775.PubMedCrossRefGoogle Scholar
  19. 19.
    Unoki H, Takahashi A, Kawaguchi T, et al.: SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 2008, 40:1098–1102.PubMedCrossRefGoogle Scholar
  20. 20.
    Zeggini E, Scott LJ, Saxena R, et al.: Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008, 40:638–645.PubMedCrossRefGoogle Scholar
  21. 21.
    Prokopenko I, Langenberg C, Florez JC, et al.: Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nat Genet 2009, 41:77–81.PubMedCrossRefGoogle Scholar
  22. 22.
    Lyssenko V, Nagorny CL, Erdos MR, et al.: Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 2009, 41:82–88.PubMedCrossRefGoogle Scholar
  23. 23.
    Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, et al.: A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 2009, 41:89–94.PubMedCrossRefGoogle Scholar
  24. 24.
    Yasuda K, Miyake K, Horikawa Y, et al.: Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 2008, 40:1092–1097.PubMedCrossRefGoogle Scholar
  25. 25.
    Marchini J, Howie B, Myers S, et al.: A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 2007, 39:906–913.PubMedCrossRefGoogle Scholar
  26. 26.
    Fan JB, Chee MS, Gunderson KL: Highly parallel genomic assays. Nat Rev Genet 2006, 7:632–644.PubMedCrossRefGoogle Scholar
  27. 27.
    Zeggini E, Rayner W, Morris AP, et al.: HapMap sample size and tagging SNP performance: an evaluation in largescale empirical and simulated data sets. Nat Genet 2005, 37:1320–1322.PubMedCrossRefGoogle Scholar
  28. 28.
    McCarroll SA, Huett A, Kuballa P, et al.: Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 2008 Aug 24 (Epub ahead of print).Google Scholar
  29. 29.
    Frayling TM: Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007, 8:657–662.PubMedCrossRefGoogle Scholar
  30. 30.
    McCarthy MI, Abecasis GR, Cardon LR, et al.: Genome wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008, 9:356–369.PubMedCrossRefGoogle Scholar
  31. 31.
    Lohmueller KE, Pearce CL, Pike M, et al.: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003, 33:177–182.PubMedCrossRefGoogle Scholar
  32. 32.
    Dabelea D, Pettitt DJ: Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab 2001, 14:1085–1091.PubMedGoogle Scholar
  33. 33.
    McCarthy MI: Casting a wider net for diabetes-susceptibility genes. Nat Genet 2008, 40:1039–1040.CrossRefGoogle Scholar
  34. 34.
    McCarroll SA, Kuruvilla FG, Korn JM, et al.: Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 2008, 40:1166–1174.PubMedCrossRefGoogle Scholar
  35. 35.
    Hill WG, Goddard ME, Visscher PM: Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet 2008, 4:e1000008.PubMedCrossRefGoogle Scholar
  36. 36.
    Smyth DJ, Cooper JD, Howson JM, 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 2008, 57:1730–1737.PubMedCrossRefGoogle Scholar
  37. 37.
    Grarup N, Rose CS, Andersson EA, et al.: Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects. Diabetes 2007, 56:3105–3111.PubMedCrossRefGoogle Scholar
  38. 38.
    Pascoe L, Tura A, Patel SK, et al.: Common variants of the novel type 2 diabetes genes, CDKAL1 and HHEX/IDE, are associated with decreased pancreatic beta-cell function. Diabetes 2007, 56:3101–3104.PubMedCrossRefGoogle Scholar
  39. 39.
    Staiger H, Machicao F, Stefan N, et al.: Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function. PLoS One 2007, 9:e832.CrossRefGoogle Scholar
  40. 40.
    Staiger H, Stancáková A, Zilinskaite J, et al.: A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations. Diabetes 2008, 57:514–517.PubMedCrossRefGoogle Scholar
  41. 41.
    Freathy RM, Timpson NJ, Lawlor DA, et al.: Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI. Diabetes 2008, 57:1419–1426.PubMedCrossRefGoogle Scholar
  42. 42.
    Leahy JL: Mary, Mary, quite contrary, how do your beta-cells fail? Diabetes 2008, 57:2563–2564.PubMedCrossRefGoogle Scholar
  43. 43.
    Lyssenko V, Lupi R, Marchetti P, et al.: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007, 117:2155–2163.PubMedCrossRefGoogle Scholar
  44. 44.
    Chimienti F, Devergnas S, Pattou F, et al.: In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci 2006, 119:4199–4206.PubMedCrossRefGoogle Scholar
  45. 45.
    Krishnamurthy J, Ramsey MR, Ligon KL, et al.: p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 2006, 443:453–457.PubMedCrossRefGoogle Scholar
  46. 46.
    Barrett JC, Hansoul S, Nicolae DL, et al.: Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008, 40:955–962.PubMedCrossRefGoogle Scholar
  47. 47.
    Thomas G, Jacobs KB, Yeager M, et al.: Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 2008, 40:310–315.PubMedCrossRefGoogle Scholar
  48. 48.
    Finkel T, Serrano M, Blasco MA: The common biology of cancer and ageing. Nature 2007, 448:767–776.PubMedCrossRefGoogle Scholar
  49. 49.
    Kasper JS, Giovannucci E: A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006, 15:2056–2062.PubMedCrossRefGoogle Scholar
  50. 50.
    Lango H; UK Type 2 Diabetes Genetics Consortium, Palmer CN, et al.: Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk. Diabetes 2008, 57:3129–3135.PubMedCrossRefGoogle Scholar
  51. 51.
    Gloyn AL, Pearson ER, Antcliff JF, et al.: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004, 350:1838–1849.PubMedCrossRefGoogle Scholar
  52. 52.
    Pearson ER, Flechtner I, Njølstad PR, et al.: Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006, 355:467–477.PubMedCrossRefGoogle Scholar
  53. 53.
    Pearson ER, Donnelly LA, Kimber C, et al.: Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007, 56:2178–2182.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalHeadington, OxfordUK

Personalised recommendations