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A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus

Nature Genetics volume 19, pages 292–296 (1998)Cite this article

Abstract

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens1,2 and studies focused on candidate genes3,4,5,6,7,8,9 have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15 . We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region10, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.

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Figure 1: Multipoint lod map of IDDM and markers on chromosome 1.
Figure 2: Multipoint lod map of IDDM and markers on chromosomes 2, 6, 8 and 10; each has at least one site with lod greater than 1.
Figure 3: Multipoint lod map of IDDM and markers on 17 chromosomes where there was no region with lod greater than 1.

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References

  1. Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 ( 1994).

    Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. Thomson, G., Robinson, W.P., Kuhner, M.K., Joe, S. & Klitz, W. HLA, insulin gene, and Gm associations with IDDM. Genet. Epidemiol. 6, 155–160 ( 1989).

    Article  CAS  Google Scholar 

  4. Julier, C. et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155 –159 (1991).

    Article  CAS  Google Scholar 

  5. Morahan, G., Huang, D., Tait, B.D., Colman, P.G. & Harrison, L.C. Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus. Science 272, 1811– 1813 (1996).

    Article  CAS  Google Scholar 

  6. Nisticò, 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).

    Article  Google Scholar 

  7. Field, L.L., Tobias, R. & Magnus, T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 8, 189– 194 (1994).

    Article  CAS  Google Scholar 

  8. Luo, D.-F. et al. Affected-sib-pair mapping of a novel susceptibility gene to insulin- dependent diabetes mellitus (IDDM8) on chromosome 6q25-27. Am. J. Hum. Genet. 57, 911–919 ( 1995).

    CAS  Google Scholar 

  9. Field, L.L., Tobias, R., Thomson, G. & Plon, S. Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3-q31. Genomics 33, 1– 8 (1996).

    Article  CAS  Google Scholar 

  10. Delépine, M. et al. Evidence of a non-MHC susceptibility locus in type I diabetes linked to HLA on chromosome 6. Am. J. Hum. Genet. 60, 174–187 (1997).

    Google Scholar 

  11. Laporte, R.E., Matsushima, M. & Chang, Y.-F. Prevalence and incidence of insulin- dependent diabetes. in Diabetes in America, (eds Harris, M.I. et al.) 37– 45 (NIH Publication No. 95-1468, 1995).

    Google Scholar 

  12. Nerup, J. et al. HL-A antigens and diabetes mellitus. Lancet 2, 864–866 (1974).

    Article  CAS  Google Scholar 

  13. Cudworth, A.G. & Woodrow, J.C. Evidence for HLA linked genes in juvenile diabetes mellitus. B.M.J. 3, 133–135 (1975).

    Article  CAS  Google Scholar 

  14. Thomson, G. A two locus model for juvenile diabetes. Ann. Hum. Genet. 43, 383–398 (1980).

    Article  CAS  Google Scholar 

  15. Risch, N. Assessing the role of HLA-linked and unlinked determinants of disease. Am. J. Hum. Genet. 40, 1–14 ( 1987).

    CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Owerbach, D. & Gabbay, K.H. The HOXD8 locus (2q31) is linked to type I diabetes. Interaction with chromosome 6 and 11 disease susceptibility genes. Diabetes 44, 132– 136 (1995).

    Article  CAS  Google Scholar 

  18. Rowe, R.E. et al. Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7. Nature Genet. 10, 240–242 (1995).

    Article  CAS  Google Scholar 

  19. Luo, D.-F. et al. Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8. Hum. Mol. Genet. 5, 693–698 (1996).

    Article  CAS  Google Scholar 

  20. Davies, J.L. et al. Saturation multipoint linkage mapping of chromosome 6q in type 1 diabetes. Hum. Mol. Genet. 5, 1071– 1074 (1996).

    Article  CAS  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. Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus. Am. J. Hum. Genet. 52, 506–516 (1993).

    CAS  Google Scholar 

  23. Copeman, J.B. et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33. Nature Genet. 9, 80–85 (1995).

    Article  CAS  Google Scholar 

  24. Owerbach, D. et al. Analysis of candidate genes for susceptibility to type 1 diabetes. A case-control and family association study of genes on chromosome 2q31-35. Diabetes 46, 1069–1074 ( 1997).

    Article  CAS  Google Scholar 

  25. Zamani, M., Pociot, F., Raeymaekers, P., Nerup, J. & Cassiman, J.J. Linkage of type I diabetes to 15q26 (IDDM3) in the Danish population. Hum. Genet. 98, 491– 496 (1996).

    Article  CAS  Google Scholar 

  26. Risch, N. Linkage strategies for genetically complex traits. III. The effect of marker polymorphism on analysis of affected relative pairs. Am. J. Hum. Genet. 46, 242–253 (1990).

    CAS  Google Scholar 

  27. Rich, S.S. Mapping genes in diabetes: genetic epidemiological perspective. Diabetes 39, 1315–1319 (1990).

    Article  CAS  Google Scholar 

  28. Lernmark, A. et al. Family cell lines available for research. Am. J. Hum. Genet. 47, 1028–1030 (1990).

    CAS  Google Scholar 

  29. Bain, S.C., Todd, J.A. & Barnett, A.H. The British Diabetic Association—Warren Repository . Autoimmunity 7, 83–85 (1990).

    Article  CAS  Google Scholar 

  30. Cox, N.J., Baker, L. & Spielman, R.S. Insulin gene sharing in sib pairs with insulin-dependent diabetes mellitus: no evidence for linkage. Am. J. Hum. Genet. 42, 167–172 ( 1988).

    CAS  Google Scholar 

  31. Holmans, P. & Craddock, N. Efficient strategies for genome scanning using maximum-likelihood affected-sib-pair analysis. Am. J. Hum. Genet. 60, 657–666 (1997).

    CAS  Google Scholar 

  32. Schwab, S.G. et al. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nature Genet. 11, 325–327 (1995).

    Article  CAS  Google Scholar 

  33. Hauser, E.R., Boehnke, M., Guo, S.-W. & Risch, N. Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations . Genet. Epidemiol. 13, 117– 137 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful for advice and assistance from R. McGinnis, M. Urbanek and L. Pinchuk, and for technical assistance by C. Blume, P. Byers, I. Edenburg, J. Ladik, J. Salvin, P. Wexler and Y. Yang. We thank the Human Biological Data Interchange and the British Diabetic Association for providing DNA samples and information about the families. This work was supported by linked NIH grants DK 46635 (P.C.), DK46627 (G.I.B.) and DK46618 (R.S.S.).

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Authors and Affiliations

  1. Virginia Mason Research Center, 1000 Seneca St., Seattle, 98101, Washington, USA

    Beth Wapelhorst, V. Annem Morrison & Brigid Stirling

  2. Department of Immunology, UW School of Medicine, Seattle, 98195, Washington, USA

    Beth Wapelhorst, V. Annem Morrison & Brigid Stirling

  3. Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Blvd, Philadelphia, 19104-6145, Pennsylvania, USA

    Kathryn J. Gogolin-Ewens, Jennifer Farmer & Sloan R. Williams

  4. Department of Genetics, Stanford University, Stanford, 94305-5120, California, USA

    David A. Hinds & Neil Risch

  5. Howard Hughes Medical Institute and Departments of Biochemistry and Molecular Biology, and Medicine, University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, 60637, Illinois, USA

    Mirna Mitra & Graeme I. Bell

  6. Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC1028, Chicago, 60637, Illinois, USA

    Nancy J. Cox

  7. Patrick Concannon

  8. Richard S. Spielman

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  1. Patrick Concannon
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Correspondence to Patrick Concannon or Richard S. Spielman.

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Concannon, P., Gogolin-Ewens, K., Hinds, D. et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nat Genet 19, 292–296 (1998). https://doi.org/10.1038/985

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