Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

A genome–wide search for human non–insulin–dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2

Abstract

Non–insulin–dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle–aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non– and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S725, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. DeFronzo, R.A., Bonadonna, R.C. & Ferrannini, E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care 15, 318–368 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. King, H. & Rewers, M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. Diabetes Care 16, 157–177 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Harris, M.I., Diabetes in America, 2nd edn. 1–13 (NIH Publication No. 95–1468,1995).

    Google Scholar 

  4. Rotter, J.I., Vadheim, C.M. & Rimoin, D.L. Diabetes mellitus. in The Genetic Basis of Common Diseases (eds King, R.A., Rotter, J.I. & Motulsky, A.G.) 413–481 (Oxford University Press, New York, 1992).

    Google Scholar 

  5. Turner, R.C., Hattersy, AT., Shaw, J.T.E & Levy, J.C. Type II diabetes: clinical aspects of molecular biological studies. Diabetes 44, 1–10 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Fajans, S.S. Maturity-onset diabetes of the young. Diabetes/Metab. Rev. 5, 579–606 (1989).

    Article  CAS  Google Scholar 

  7. Vaxillaire, M. et al. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nature Genet. 9, 418–423 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Byrne, M.M. et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 44, 699–704(1995).

    Article  CAS  PubMed  Google Scholar 

  9. Froguel, P. et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N. Engl. J. Med. 328, 697–702 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Grupe, A. et al. Transgenic knockouts reveal a critical requirement for pancreatic β cell glucokinase in maintaining glucose homeostasis. Cell 83, 69–78 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Ballinger, S.W. et al. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondria! DNA deletion. Nature Genet. 1, 11–15 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. van den Ouweland, J.M.V. et al. gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet. 1, 368–371 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Steiner, D.F., Tager, H.S., Nanjo, K., Chan, S.J. & Rubenstein, A.H. Familial syndromes of hyperproinsulinemia and hyperinsulinemia with mild diabetes In The Metabolic and Molecular Bases of Inherited Disease, (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 897–904 (McGraw-Hill, Inc., New York, 1995).

    Google Scholar 

  14. Taylor, S.I. Diabetes mellitus. in The Metabolic and Molecular Bases of Inherited Disease, (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.)843–896 (McGraw-Hill, Inc., New York, 1995).

    Google Scholar 

  15. Hamman, R.F. Genetic and environmental determinants of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Metab. Rev. 8, 287–338 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Lander, E. L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Hanis, C.L. et al. Mortality of Mexican Americans with NIDDM: retinopathy and other predictors in Starr County, Texas. Diabetes Care 16, 82–89 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Hanis, C.L., Hewett-Emmett, D., Bertin, T.K. & Schull, W.J. Origins of U.S.Hispanics: implications for diabetes. Diabetes Care 14, 618–627 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Holmans, P. Asymptotic properties of affected-sib-pair linkage analysis. Am. J. Hum. Genet. 52, 362–374 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Holmans, P. & Clayton, D. Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers. Am. J. Hum. Genet. 57, 1221–1232 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bishop, D.T. & Williamson, J.A. The power of identity-by-state methods for linkage analysis. Am. J. Hum. Genet. 46, 254–265 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Risch, N. Exclusion mapping for complex diseases. Am. J. Hum. Genet. 53, A185 (1993).

    Google Scholar 

  23. Suarez, B.K. & Hodge, S.E. A simple method to detect linkage for rare recessive diseases: an application to juvenile diabetes. Clin. Genet. 15, 126–136 (1979).

    Article  CAS  PubMed  Google Scholar 

  24. Hodge, S.E. & Elston, R.C., Lods, wrods, and mods: the interpretation of lod scores calculated under different models. Genet. Epidemiol. 11, 329–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Curtis, D. & Sham, P.C. Model-free linkage analysis using likelihoods. Am. J. Hum. Genet. 57, 703–716 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Risch, N. Linkage strategies for genetically complex traits. II. the power of affected relative pairs. Am. J. Hum. Genet. 46, 229–241 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gyapay, G. et al.The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Norman, R.A., Bogardus, C. & Ravussin, E. Linkage between obesity and a marker near the tumor necrosis factor-α locus in Pima Indians. J. Clin. Invest. 96, 158–162 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Walston, J. et al. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic-receptor gene. N. Engl. J. Med. 333, 342–347 (1995).

    Article  Google Scholar 

  31. Widen, E. et al. Association of polymorphism in the β3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N. Engl. J. Med. 333, 348–351 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Clement, K. et al. Genetic variation in the β3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N. Engl. J. Med. 333, 352–354 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Davies, J.L. 1 diabetes susceptibility genes. Nature 371, 130–136 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Hashimoto, L. et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 371, 161–164 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Todd, J.A. Genetic analysis of type 1 diabetes using whole genome approaches. Proc. Natl. Acad. Sci. USA 92, 8560–8565 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hager, J. et al. A missense mutation in the glucagon receptor gene is associated with non- insulin dependent diabetes mellitus. Nature Genet. 9, 299–304 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Thompson, D.B. et al. Evidence for linkage between a region on chromosome 1 p and the acute insulin response in Pima Indians. Diabetes 44, 478–481 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Prochazka, M. et al. Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42, 514–619 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Iwasaki, N. Identification of microsatellite markers near the human genes encoding the β- cell ATP-sensitive K+ channel and linkage studies with NIDDM in Japanese. Diabetes 45, 267–269 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Hudson, T.J. et al.An STS-based map of the human genome. Science 270, 1945–1954 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Harris, M.I., classification, diagnositic criteria, and screening for diabetes, in Diabetes in America, 2nd edn. 15–36 (NIH Publication No. 95-1468,1995).

    Google Scholar 

  42. Fasman, K.H., Cuticchia, A.J. & Kingsbury, D.T. The GDB human genome data base anno 1994. Nucl. Adds Res. 22, 3462–3469 (1994).

    Article  CAS  Google Scholar 

  43. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37 482–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Yamagata, K. et al.Searching for NIDDM susceptibility genes: studies of genes with triplet repeats expressed in skeletal muscle. Diabetologia(in the press).

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanis, C., Boerwinkle, E., Chakraborty, R. et al. A genome–wide search for human non–insulin–dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13, 161–166 (1996). https://doi.org/10.1038/ng0696-161

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0696-161

Search

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