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


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.


  1. 1

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

  2. 2

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

  3. 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).

  4. 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).

  5. 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).

  6. 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).

  7. 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).

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 12

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

  13. 13

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

  14. 14

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

  15. 15

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

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 20

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

  21. 21

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

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 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).

  27. 27

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

  28. 28

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

  29. 29

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

  30. 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).

  31. 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).

  32. 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).

  33. 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).

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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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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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