Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Sep 12;92(19):8560–8565. doi: 10.1073/pnas.92.19.8560

Genetic analysis of type 1 diabetes using whole genome approaches.

J A Todd 1
PMCID: PMC41006  PMID: 7567975

Abstract

Whole genome linkage analysis of type 1 diabetes using affected sib pair families and semi-automated genotyping and data capture procedures has shown how type 1 diabetes is inherited. A major proportion of clustering of the disease in families can be accounted for by sharing of alleles at susceptibility loci in the major histocompatibility complex on chromosome 6 (IDDM1) and at a minimum of 11 other loci on nine chromosomes. Primary etiological components of IDDM1, the HLA-DQB1 and -DRB1 class II immune response genes, and of IDDM2, the minisatellite repeat sequence in the 5' regulatory region of the insulin gene on chromosome 11p15, have been identified. Identification of the other loci will involve linkage disequilibrium mapping and sequencing of candidate genes in regions of linkage.

Full text

PDF
8564

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aanstoot H. J., Sigurdsson E., Jaffe M., Shi Y., Christgau S., Grobbee D., Bruining G. J., Molenaar J. L., Hofman A., Baekkeskov S. Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population. Diabetologia. 1994 Sep;37(9):917–924. doi: 10.1007/BF00400948. [DOI] [PubMed] [Google Scholar]
  2. Bain S. C., Prins J. B., Hearne C. M., Rodrigues N. R., Rowe B. R., Pritchard L. E., Ritchie R. J., Hall J. R., Undlien D. E., Ronningen K. S. Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nat Genet. 1992 Nov;2(3):212–215. doi: 10.1038/ng1192-212. [DOI] [PubMed] [Google Scholar]
  3. Bain S. C., Rowe B. R., Barnett A. H., Todd J. A. Parental origin of diabetes-associated HLA types in sibling pairs with type I diabetes. Diabetes. 1994 Dec;43(12):1462–1468. doi: 10.2337/diab.43.12.1462. [DOI] [PubMed] [Google Scholar]
  4. Bell G. I., Horita S., Karam J. H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984 Feb;33(2):176–183. doi: 10.2337/diab.33.2.176. [DOI] [PubMed] [Google Scholar]
  5. Bingley P. J., Bonifacio E., Gale E. A. Can we really predict IDDM? Diabetes. 1993 Feb;42(2):213–220. doi: 10.2337/diab.42.2.213. [DOI] [PubMed] [Google Scholar]
  6. Cookson W. O., Sharp P. A., Faux J. A., Hopkin J. M. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet. 1989 Jun 10;1(8650):1292–1295. doi: 10.1016/s0140-6736(89)92687-1. [DOI] [PubMed] [Google Scholar]
  7. Copeman J. B., Cucca F., Hearne C. M., Cornall R. J., Reed P. W., Rønningen K. S., Undlien D. E., Nisticò L., Buzzetti R., Tosi R. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33. Nat Genet. 1995 Jan;9(1):80–85. doi: 10.1038/ng0195-80. [DOI] [PubMed] [Google Scholar]
  8. Cudworth A. G., Woodrow J. C. HL-A system and diabetes mellitus. Diabetes. 1975 Apr;24(4):345–349. doi: 10.2337/diab.24.4.345. [DOI] [PubMed] [Google Scholar]
  9. Davies J. L., Kawaguchi Y., Bennett S. T., Copeman J. B., Cordell H. J., Pritchard L. E., Reed P. W., Gough S. C., Jenkins S. C., Palmer S. M. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994 Sep 8;371(6493):130–136. doi: 10.1038/371130a0. [DOI] [PubMed] [Google Scholar]
  10. DeChiara T. M., Efstratiadis A., Robertson E. J. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990 May 3;345(6270):78–80. doi: 10.1038/345078a0. [DOI] [PubMed] [Google Scholar]
  11. Dizier M. H., Babron M. C., Clerget-Darpoux F. Interactive effect of two candidate genes in a disease: extension of the marker-association-segregation chi(2) method. Am J Hum Genet. 1994 Nov;55(5):1042–1049. [PMC free article] [PubMed] [Google Scholar]
  12. Drell D. W., Notkins A. L. Multiple immunological abnormalities in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987 Mar;30(3):132–143. doi: 10.1007/BF00274217. [DOI] [PubMed] [Google Scholar]
  13. Dörner G., Thoelke H., Mohnike A., Schneider H. High food supply in perinatal life appears to favour the development of insulin-treated diabetes mellitus (ITDM) in later life. Exp Clin Endocrinol. 1985 Feb;85(1):1–6. doi: 10.1055/s-0029-1210414. [DOI] [PubMed] [Google Scholar]
  14. Eisenbarth G. S. Mouse or man. Is GAD the cause of type I diabetes? Diabetes Care. 1994 Jun;17(6):605–607. doi: 10.2337/diacare.17.6.605. [DOI] [PubMed] [Google Scholar]
  15. Falk C. T., Rubinstein P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet. 1987 Jul;51(Pt 3):227–233. doi: 10.1111/j.1469-1809.1987.tb00875.x. [DOI] [PubMed] [Google Scholar]
  16. Field L. L. Non-HLA region genes in insulin dependent diabetes mellitus. Baillieres Clin Endocrinol Metab. 1991 Sep;5(3):413–438. doi: 10.1016/s0950-351x(05)80139-9. [DOI] [PubMed] [Google Scholar]
  17. Field L. L., Tobias R., Magnus T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nat Genet. 1994 Oct;8(2):189–194. doi: 10.1038/ng1094-189. [DOI] [PubMed] [Google Scholar]
  18. Geenen V., Achour I., Robert F., Vandersmissen E., Sodoyez J. C., Defresne M. P., Boniver J., Lefebvre P. J., Franchimont P. Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily. Thymus. 1993 Mar;21(2):115–127. [PubMed] [Google Scholar]
  19. Ghosh S., Palmer S. M., Rodrigues N. R., Cordell H. J., Hearne C. M., Cornall R. J., Prins J. B., McShane P., Lathrop G. M., Peterson L. B. Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet. 1993 Aug;4(4):404–409. doi: 10.1038/ng0893-404. [DOI] [PubMed] [Google Scholar]
  20. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  21. Hamer D. H., Hu S., Magnuson V. L., Hu N., Pattatucci A. M. A linkage between DNA markers on the X chromosome and male sexual orientation. Science. 1993 Jul 16;261(5119):321–327. doi: 10.1126/science.8332896. [DOI] [PubMed] [Google Scholar]
  22. Hashimoto L., Habita C., Beressi J. P., Delepine M., Besse C., Cambon-Thomsen A., Deschamps I., Rotter J. I., Djoulah S., James M. R. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature. 1994 Sep 8;371(6493):161–164. doi: 10.1038/371161a0. [DOI] [PubMed] [Google Scholar]
  23. Hilbert P., Lindpaintner K., Beckmann J. S., Serikawa T., Soubrier F., Dubay C., Cartwright P., De Gouyon B., Julier C., Takahasi S. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 1991 Oct 10;353(6344):521–529. doi: 10.1038/353521a0. [DOI] [PubMed] [Google Scholar]
  24. Hästbacka J., de la Chapelle A., Kaitila I., Sistonen P., Weaver A., Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. doi: 10.1038/ng1192-204. [DOI] [PubMed] [Google Scholar]
  25. Ikegami H., Kawaguchi Y., Ueda H., Fukuda M., Takakawa K., Fujioka Y., Fujisawa T., Uchida K., Ogihara T. MHC-linked diabetogenic gene of the NOD mouse: molecular mapping of the 3' boundary of the diabetogenic region. Biochem Biophys Res Commun. 1993 Apr 30;192(2):677–682. doi: 10.1006/bbrc.1993.1468. [DOI] [PubMed] [Google Scholar]
  26. Jacob H. J., Lindpaintner K., Lincoln S. E., Kusumi K., Bunker R. K., Mao Y. P., Ganten D., Dzau V. J., Lander E. S. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell. 1991 Oct 4;67(1):213–224. doi: 10.1016/0092-8674(91)90584-l. [DOI] [PubMed] [Google Scholar]
  27. Johansson C., Samuelsson U., Ludvigsson J. A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1994 Jan;37(1):91–94. doi: 10.1007/BF00428783. [DOI] [PubMed] [Google Scholar]
  28. Jorde L. B. Linkage disequilibrium as a gene-mapping tool. Am J Hum Genet. 1995 Jan;56(1):11–14. [PMC free article] [PubMed] [Google Scholar]
  29. Julier C., Hyer R. N., Davies J., Merlin F., Soularue P., Briant L., Cathelineau G., Deschamps I., Rotter J. I., Froguel P. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature. 1991 Nov 14;354(6349):155–159. doi: 10.1038/354155a0. [DOI] [PubMed] [Google Scholar]
  30. Julier C., Lucassen A., Villedieu P., Delepine M., Levy-Marchal C., Danzé P. M., Bianchi F., Boitard C., Froguel P., Bell J. Multiple DNA variant association analysis: application to the insulin gene region in type I diabetes. Am J Hum Genet. 1994 Dec;55(6):1247–1254. [PMC free article] [PubMed] [Google Scholar]
  31. Kaprio J., Tuomilehto J., Koskenvuo M., Romanov K., Reunanen A., Eriksson J., Stengård J., Kesäniemi Y. A. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia. 1992 Nov;35(11):1060–1067. doi: 10.1007/BF02221682. [DOI] [PubMed] [Google Scholar]
  32. Kennedy G. C., German M. S., Rutter W. J. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet. 1995 Mar;9(3):293–298. doi: 10.1038/ng0395-293. [DOI] [PubMed] [Google Scholar]
  33. Khalil I., d'Auriol L., Gobet M., Morin L., Lepage V., Deschamps I., Park M. S., Degos L., Galibert F., Hors J. A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest. 1990 Apr;85(4):1315–1319. doi: 10.1172/JCI114569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kruglyak L., Lander E. S. High-resolution genetic mapping of complex traits. Am J Hum Genet. 1995 May;56(5):1212–1223. [PMC free article] [PubMed] [Google Scholar]
  35. Lander E. S., Botstein D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics. 1989 Jan;121(1):185–199. doi: 10.1093/genetics/121.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  37. Leslie R. D., Elliott R. B. Early environmental events as a cause of IDDM. Evidence and implications. Diabetes. 1994 Jul;43(7):843–850. doi: 10.2337/diab.43.7.843. [DOI] [PubMed] [Google Scholar]
  38. Lucassen A. M., Julier C., Beressi J. P., Boitard C., Froguel P., Lathrop M., Bell J. I. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet. 1993 Jul;4(3):305–310. doi: 10.1038/ng0793-305. [DOI] [PubMed] [Google Scholar]
  39. Lucassen A. M., Screaton G. R., Julier C., Elliott T. J., Lathrop M., Bell J. I. Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype. Hum Mol Genet. 1995 Apr;4(4):501–506. doi: 10.1093/hmg/4.4.501. [DOI] [PubMed] [Google Scholar]
  40. Matsushita S., Takahashi K., Motoki M., Komoriya K., Ikagawa S., Nishimura Y. Allele specificity of structural requirement for peptides bound to HLA-DRB1*0405 and -DRB1*0406 complexes: implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndrome. J Exp Med. 1994 Sep 1;180(3):873–883. doi: 10.1084/jem.180.3.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Muir A., Peck A., Clare-Salzler M., Song Y. H., Cornelius J., Luchetta R., Krischer J., Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest. 1995 Feb;95(2):628–634. doi: 10.1172/JCI117707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Nerup J., Platz P., Andersen O. O., Christy M., Lyngsoe J., Poulsen J. E., Ryder L. P., Nielsen L. S., Thomsen M., Svejgaard A. HL-A antigens and diabetes mellitus. Lancet. 1974 Oct 12;2(7885):864–866. doi: 10.1016/s0140-6736(74)91201-x. [DOI] [PubMed] [Google Scholar]
  43. Olmos P., A'Hern R., Heaton D. A., Millward B. A., Risley D., Pyke D. A., Leslie R. D. The significance of the concordance rate for type 1 (insulin-dependent) diabetes in identical twins. Diabetologia. 1988 Oct;31(10):747–750. doi: 10.1007/BF00274777. [DOI] [PubMed] [Google Scholar]
  44. 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. 1995 Jan;44(1):132–136. doi: 10.2337/diab.44.1.132. [DOI] [PubMed] [Google Scholar]
  45. Peterson A. C., Di Rienzo A., Lehesjoki A. E., de la Chapelle A., Slatkin M., Freimer N. B. The distribution of linkage disequilibrium over anonymous genome regions. Hum Mol Genet. 1995 May;4(5):887–894. doi: 10.1093/hmg/4.5.887. [DOI] [PubMed] [Google Scholar]
  46. Polychronakos C., Kukuvitis A., Giannoukakis N., Colle E. Parental imprinting effect at the INS-IGF2 diabetes susceptibility locus. Diabetologia. 1995 Jun;38(6):715–719. doi: 10.1007/BF00401845. [DOI] [PubMed] [Google Scholar]
  47. Pritchard L. E., Kawaguchi Y., Reed P. W., Copeman J. B., Davies J. L., Barnett A. H., Bain S. C., Todd J. A. Analysis of the CD3 gene region and type 1 diabetes: application of fluorescence-based technology to linkage disequilibrium mapping. Hum Mol Genet. 1995 Feb;4(2):197–202. doi: 10.1093/hmg/4.2.197. [DOI] [PubMed] [Google Scholar]
  48. Pugliese A., Awdeh Z. L., Alper C. A., Jackson R. A., Eisenbarth G. S. The paternally inherited insulin gene B allele (1,428 FokI site) confers protection from insulin-dependent diabetes in families. J Autoimmun. 1994 Oct;7(5):687–694. doi: 10.1006/jaut.1994.1053. [DOI] [PubMed] [Google Scholar]
  49. Raffel L. J., Vadheim C. M., Roth M. P., Klein R., Moss S. E., Rotter J. I. The 5' insulin gene polymorphism and the genetics of vascular complications in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1991 Sep;34(9):680–683. doi: 10.1007/BF00400999. [DOI] [PubMed] [Google Scholar]
  50. Reed P. W., Davies J. L., Copeman J. B., Bennett S. T., Palmer S. M., Pritchard L. E., Gough S. C., Kawaguchi Y., Cordell H. J., Balfour K. M. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nat Genet. 1994 Jul;7(3):390–395. doi: 10.1038/ng0794-390. [DOI] [PubMed] [Google Scholar]
  51. Reich E. P., von Grafenstein H., Barlow A., Swenson K. E., Williams K., Janeway C. A., Jr Self peptides isolated from MHC glycoproteins of non-obese diabetic mice. J Immunol. 1994 Mar 1;152(5):2279–2288. [PubMed] [Google Scholar]
  52. Rich S. S. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes. 1990 Nov;39(11):1315–1319. doi: 10.2337/diab.39.11.1315. [DOI] [PubMed] [Google Scholar]
  53. Risch N. A note on multiple testing procedures in linkage analysis. Am J Hum Genet. 1991 Jun;48(6):1058–1064. [PMC free article] [PubMed] [Google Scholar]
  54. Risch N. Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet. 1987 Jan;40(1):1–14. [PMC free article] [PubMed] [Google Scholar]
  55. Risch N. Genetic linkage: interpreting lod scores. Science. 1992 Feb 14;255(5046):803–804. doi: 10.1126/science.1536004. [DOI] [PubMed] [Google Scholar]
  56. Risch N., Ghosh S., Todd J. A. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Sep;53(3):702–714. [PMC free article] [PubMed] [Google Scholar]
  57. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222–228. [PMC free article] [PubMed] [Google Scholar]
  58. Risch N., Zhang H. Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science. 1995 Jun 16;268(5217):1584–1589. doi: 10.1126/science.7777857. [DOI] [PubMed] [Google Scholar]
  59. Risch N., de Leon D., Ozelius L., Kramer P., Almasy L., Singer B., Fahn S., Breakefield X., Bressman S. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet. 1995 Feb;9(2):152–159. doi: 10.1038/ng0295-152. [DOI] [PubMed] [Google Scholar]
  60. Rise M. L., Frankel W. N., Coffin J. M., Seyfried T. N. Genes for epilepsy mapped in the mouse. Science. 1991 Aug 9;253(5020):669–673. doi: 10.1126/science.1871601. [DOI] [PubMed] [Google Scholar]
  61. Rotter J. I. The modes of inheritance of insulin-dependent diabetes mellitus or the genetics of IDDM, no longer a nightmare but still a headache. Am J Hum Genet. 1981 Nov;33(6):835–851. [PMC free article] [PubMed] [Google Scholar]
  62. Rowe R. E., Wapelhorst B., Bell G. I., Risch N., Spielman R. S., Concannon P. Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7. Nat Genet. 1995 Jun;10(2):240–242. doi: 10.1038/ng0695-240. [DOI] [PubMed] [Google Scholar]
  63. Schaid D. J., Sommer S. S. Comparison of statistics for candidate-gene association studies using cases and parents. Am J Hum Genet. 1994 Aug;55(2):402–409. [PMC free article] [PubMed] [Google Scholar]
  64. Sheil J. M., Shepherd S. E., Klimo G. F., Paterson Y. Identification of an autologous insulin B chain peptide as a target antigen for H-2Kb-restricted cytotoxic T lymphocytes. J Exp Med. 1992 Feb 1;175(2):545–552. doi: 10.1084/jem.175.2.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Singal D. P., Blajchman M. A. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes. 1973 Jun;22(6):429–432. doi: 10.2337/diab.22.6.429. [DOI] [PubMed] [Google Scholar]
  66. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  67. Theofilopoulos A. N. The basis of autoimmunity: Part II. Genetic predisposition. Immunol Today. 1995 Mar;16(3):150–159. doi: 10.1016/0167-5699(95)80133-2. [DOI] [PubMed] [Google Scholar]
  68. Thomson G. Identifying complex disease genes: progress and paradigms. Nat Genet. 1994 Oct;8(2):108–110. doi: 10.1038/ng1094-108. [DOI] [PubMed] [Google Scholar]
  69. Thomson G., Robinson W. P., Kuhner M. K., Joe S., Klitz W. HLA and insulin gene associations with IDDM. Genet Epidemiol. 1989;6(1):155–160. doi: 10.1002/gepi.1370060129. [DOI] [PubMed] [Google Scholar]
  70. Todd J. A. A protective role of the environment in the development of type 1 diabetes? Diabet Med. 1991 Dec;8(10):906–910. doi: 10.1111/j.1464-5491.1991.tb01528.x. [DOI] [PubMed] [Google Scholar]
  71. Todd J. A., Aitman T. J., Cornall R. J., Ghosh S., Hall J. R., Hearne C. M., Knight A. M., Love J. M., McAleer M. A., Prins J. B. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. doi: 10.1038/351542a0. [DOI] [PubMed] [Google Scholar]
  72. Todd J. A., Bain S. C. A practical approach to identification of susceptibility genes for IDDM. Diabetes. 1992 Sep;41(9):1029–1034. doi: 10.2337/diab.41.9.1029. [DOI] [PubMed] [Google Scholar]
  73. Todd J. A., Bell J. I., McDevitt H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]
  74. Todd J. A. Genetic control of autoimmunity in type 1 diabetes. Immunol Today. 1990 Apr;11(4):122–129. doi: 10.1016/0167-5699(90)90049-f. [DOI] [PubMed] [Google Scholar]
  75. Todd J. A. Lawrence Lecture. The Emperor's new genes: 1993 RD Lawrence Lecture. Diabet Med. 1994 Jan-Feb;11(1):6–16. doi: 10.1111/j.1464-5491.1994.tb00222.x. [DOI] [PubMed] [Google Scholar]
  76. Todd J. A., Mijovic C., Fletcher J., Jenkins D., Bradwell A. R., Barnett A. H. Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature. 1989 Apr 13;338(6216):587–589. doi: 10.1038/338587a0. [DOI] [PubMed] [Google Scholar]
  77. Tomfohrde J., Silverman A., Barnes R., Fernandez-Vina M. A., Young M., Lory D., Morris L., Wuepper K. D., Stastny P., Menter A. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science. 1994 May 20;264(5162):1141–1145. doi: 10.1126/science.8178173. [DOI] [PubMed] [Google Scholar]
  78. Undlien D. E., Bennett S. T., Todd J. A., Akselsen H. E., Ikäheimo I., Reijonen H., Knip M., Thorsby E., Rønningen K. S. Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene. Diabetes. 1995 Jun;44(6):620–625. doi: 10.2337/diab.44.6.620. [DOI] [PubMed] [Google Scholar]
  79. Vandewalle C. L., Decraene T., Schuit F. C., De Leeuw I. H., Pipeleers D. G., Gorus F. K. Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry. Diabetologia. 1993 Nov;36(11):1155–1162. doi: 10.1007/BF00401060. [DOI] [PubMed] [Google Scholar]
  80. Wang S., Sun C. E., Walczak C. A., Ziegle J. S., Kipps B. R., Goldin L. R., Diehl S. R. Evidence for a susceptibility locus for schizophrenia on chromosome 6pter-p22. Nat Genet. 1995 May;10(1):41–46. doi: 10.1038/ng0595-41. [DOI] [PubMed] [Google Scholar]
  81. Warram J. H., Krolewski A. S., Gottlieb M. S., Kahn C. R. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med. 1984 Jul 19;311(3):149–152. doi: 10.1056/NEJM198407193110304. [DOI] [PubMed] [Google Scholar]
  82. Wicker L. S., Todd J. A., Peterson L. B. Genetic control of autoimmune diabetes in the NOD mouse. Annu Rev Immunol. 1995;13:179–200. doi: 10.1146/annurev.iy.13.040195.001143. [DOI] [PubMed] [Google Scholar]
  83. Wucherpfennig K. W., Strominger J. L. Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases. J Exp Med. 1995 May 1;181(5):1597–1601. doi: 10.1084/jem.181.5.1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. van der Auwera B. J., Heimberg H., Schrevens A. F., van Waeyenberge C., Flament J., Schuit F. C. 5' insulin gene polymorphism confers risk to IDDM independently of HLA class II susceptibility. Diabetes. 1993 Jun;42(6):851–854. doi: 10.2337/diab.42.6.851. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES