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.

  • Letter
  • Published:

Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families

Nature Genetics volume 14, pages 90–94 (1996)Cite this article

Abstract

Non–insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide1,2 and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion3. Family studies point to a major genetic component4–6, but specific susceptibility genes have not yet been identified — except for rare early–onset forms with monogenic7–10 or mito–chondrial11 inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome–wide scan using non–parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 × 10−5) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early–onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age–of–onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. King, H. & Zimmet, P. Trends in the prevalence and incidence of diabetes: non-insulin-dependent diabetes mellitus. Wld. Hlth. Statist. Quart. 41, 190–196 (1988).

    CAS  Google Scholar 

  2. Harris, M.I., Klein, R., Welborn, T.A. & Knuiman, M.W. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 15, 815–819 (1992).

    Article  CAS  Google Scholar 

  3. DeFronzo, R.A., Lilly Lecture 1987: the triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37, 667–687 (1988).

    Article  CAS  Google Scholar 

  4. Newman, B., Selby, J.V., King, M.C., Slemenda, C., Fabsitz, R. & Friedman, G.D. Concordance for Type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30, 763–768 (1987).

    Article  CAS  Google Scholar 

  5. Köbberling, J. Studies on the genetic heterogeneity of diabetes mellitus. Diabetologia 7, 46–49 (1971).

    Article  Google Scholar 

  6. Cook, J.T.E. et al. Segregation analysis of NIDDM in caucausian families. Diabetologia 37, 1231–1240 (1994).

    Article  CAS  Google Scholar 

  7. Bell, G.I. et al. Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype is linked to DNA polymorphism on human chromosome 20q. Proc. Natl. Acad. Sci. USA 88, 1484–1488 (1991).

    Article  CAS  Google Scholar 

  8. Froguel, P. et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162–164 (1992).

    Article  CAS  Google Scholar 

  9. Hattersley, A.T. et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 339, 1307–1310 (1992).

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Van den Ouwenland, J.M.W. et al. Mutation in mitochondrial tRNA Leu (UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet. 1, 368–371 (1992).

    Article  Google Scholar 

  12. Virtaranta-Knowles, K., Sistonen, P. & Nevanlinna, H.R. A population genetic study in Finland: comparison of the Finnish-and Swedish-speaking populations. Hum. Hered. 41, 248–264 (1991).

    Article  CAS  Google Scholar 

  13. Eriksson, J., Forsen, B., Häggblom, M., Teppo, A.-M. & Groop, L. Clinical and metabolic characteristics of Type 1 and Type 2 diabetes: An epidemiological study from the Närpes Community in Western Finland. Diabetic Med. 9, 654–660 (1992).

    Article  CAS  Google Scholar 

  14. Newman, B., Austin, M.A., Lee, M. & King, M.-C. Inheritance of human breast cancer: Evidence for autosomal dominant transmission in high-risk families. Proc. Natl. Acad. Sci USA 85, 3044–3048 (1988).

    Article  CAS  Google Scholar 

  15. Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17p21. Science 250, 1684–1689 (1990).

    Article  CAS  Google Scholar 

  16. Peltomäki, P. et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810–812. (1993).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Murray, J.C. et al. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science 265, 2049–2054 (1994).

    Article  CAS  Google Scholar 

  20. Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Cerasi, E., Efendic, S. & Luft, R. Dose-response relation between plasma-insulin and blood-glucose loads in prediabetic and diabetic subjects. Lancet i, 794–797 (1973).

    Article  Google Scholar 

  23. O'Rahilly, S.P. et al. Beta-cell dysfunction, rather than insulin sensitivity, is the primary defect in Type 2 diabetes. Lancet ii, 360–364 (1986).

    Article  Google Scholar 

  24. Lillioja, S. et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N. Engl. J. Med. 318, 1217–1225 (1988).

    Article  CAS  Google Scholar 

  25. Haffner, S.M., Stern, M.P., Dunn, J., Mobley, M., Blackwell, J. & Bergman, R.N. Diminished insulin sensitivity and increased insulin response in nonobese nondiabetic Mexican Americans. Metabolism 39, 842–847 (1990).

    Article  CAS  Google Scholar 

  26. Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994).

    Article  CAS  Google Scholar 

  27. Kahn, S.E. et al. Quantification of the relationship between insulin sensitivity and β-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42, 1663–1672 (1993).

    Article  CAS  Google Scholar 

  28. Yki-Järvinen, H. Acute and chronic effects of hyperglycemia on glucose metabolism. Diabetologia 33, 579–585 (1990).

    Article  Google Scholar 

  29. Menzel, S. et al. Localization of MODY3 to a 5-cM region of human chromosome 12. Diabetes 44, 1408–1413 (1995).

    Article  CAS  Google Scholar 

  30. Lesage, S. et al. Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM. Diabetes 44, 1243–1247 (1995).

    Article  CAS  Google Scholar 

  31. Hanis, C.L. et al. A genome-wide search for human non-insulin-dependent (type2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet. 13, 161–166 (1996).

    Article  CAS  Google Scholar 

  32. Wold Health Organization. Diabetes mellitus. Report of a WHO study Group. Technical report Series, WHO, Geneva (1985).

  33. Charles, M.A. et al. Risk factors for NIDDM in white population. Paris prospective study. Diabetes 40, 796–799 (1991).

    Article  CAS  Google Scholar 

  34. Saad, M.F., Knowler, W.C., Pettitt, D.J., Nelson, R.G., Mott, D.M. & Bennett, P.H. The natural history of impaired glucose tolerance in the Pima Indians. N. Engl. J. Med. 319, 1500–1506 (1988).

    Article  CAS  Google Scholar 

  35. Sartor, G., Schersten, B., Cariström, S., Melander, A. & Å. Persson, G. Ten-year follow-up of subjects with impaired glucose tolerance. Prevention of diabetes by tolbutamide and diet regulation. Diabetes 29, 41–19 (1980).

    Article  CAS  Google Scholar 

  36. Dietrich, W. et al. A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nature Genet 7, 220–245 (1994).

    Article  CAS  Google Scholar 

  37. Hastbacka, J. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1992).

    Article  CAS  Google Scholar 

  38. Weber, J.L. & Wong, C. Mutation of human short tandem repeats. Hum. Mol. Genet. 2, 1123–1128 (1993).

    Article  CAS  Google Scholar 

  39. Galli, J. et al. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nature Genet 12, 31–37 (1996).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Melanie M. Mahtani and Elisabeth Widén: M.M.M. & E.W. contributed equally to this work.

Authors and Affiliations

  1. Whitehead Institute/or Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, 02142, USA

    Melanie M. Mahtani, Elisabeth Widén, Mark McCarthy, Mark Daly, Andrew Kirby, Leonid Kruglyak, Mary Pat Reeve-Daly, Alix Weaver, Thomas Brettin & Eric S. Lander

  2. Wallenberg Laboratory, Department of Endocrinology, Lund University, Malmö, Sweden

    Elisabeth Widén, Markku Lehto, Timo Kanninen, Maikki Parkkonen & Leif C. Groop

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Eric S. Lander

  4. Millennium Pharmaceuticals Inc., Cambridge, Massachusetts, 02139, USA

    Jeffrey Thomas, James Brayer, Barbara Bryant, Gayun Chan, Kevin Munnelly & Geoffrey Duyk

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

    Carol Forsblom

Authors
  1. Melanie M. Mahtani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabeth Widén
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markku Lehto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James Brayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Barbara Bryant
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gayun Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carol Forsblom
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Timo Kanninen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andrew Kirby
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Leonid Kruglyak
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kevin Munnelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Maikki Parkkonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mary Pat Reeve-Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Alix Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Thomas Brettin
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Geoffrey Duyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Eric S. Lander
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Leif C. Groop
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mahtani, M., Widén, E., Lehto, M. et al. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet 14, 90–94 (1996). https://doi.org/10.1038/ng0996-90

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0996-90

This article is cited by

Search

Advanced 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