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Understanding type 1 diabetes through genetics: advances and prospects

Nature Reviews Genetics volume 12, pages 781–792 (2011)Cite this article

Subjects

Key Points

  • Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic β-cells by T lymphocytes. It is one of the most heritable of complex traits.

  • A large part of the genetic risk for T1D (almost half) is due to alleles of the human leukocyte antigen (HLA) genes, primarily of the class II HLAs. These alleles are common in the general population but are enriched in T1D and as a result are carried by the vast majority of T1D cases.

  • Insulin is a major autoantigen in T1D. After HLA, variants of the gene encoding insulin are responsible for the second strongest genetic effect on T1D risk. The predisposing alleles are associated with reduced insulin expression in the thymus, hypothesized to lead to defective development of central self-tolerance.

  • Candidate gene approaches and genome-wide association studies have revealed over forty genetic associations with T1D, some of which involve known genes of the innate and adaptive immune responses. Where the functional effect of the T1D-associated polymorphism is known, it appears to inhibit T cell activation.

  • Known genetic associations explain almost three-quarters of the sibling relative risk and genetic prediction is approaching metrics that are meaningful in planning application of preventive interventions.

  • Gene–gene and especially gene–environment interactions will need to be studied in the future. This will require the assembly of large data and sample resources.

Abstract

Starting with early crucial discoveries of the role of the major histocompatibility complex, genetic studies have long had a role in understanding the biology of type 1 diabetes (T1D), which is one of the most heritable common diseases. Recent genome-wide association studies (GWASs) have given us a clearer picture of the allelic architecture of genetic susceptibility to T1D. Fine mapping and functional studies are gradually revealing the complex mechanisms whereby immune self-tolerance is lost, involving multiple aspects of adaptive immunity. The triggering of these events by dysregulation of the innate immune system has also been implicated by genetic evidence. Finally, genetic prediction of T1D risk is showing promise of use for preventive strategies.

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Figure 1: Locus-specific λS for T1D associations outside the MHC.
Figure 2: The effect of selected T1D-associated variants on T cell activation.
Figure 3: The receiver operating characteristic (ROC) curve for the known T1D loci.

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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).

    CAS  PubMed  Google Scholar 

  2. Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S. & Orban, T. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 359, 2849–2850 (2008).

    CAS  PubMed  Google Scholar 

  3. Steck, A. K. et al. Secondary attack rate of type 1 diabetes in Colorado families. Diabetes Care 28, 296–300 (2005).

    PubMed  Google Scholar 

  4. Patterson, C. C., Dahlquist, G. G., Gyurus, E., Green, A. & Soltesz, G. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 373, 2027–2033 (2009).

    PubMed  Google Scholar 

  5. Onkamo, P., Vaananen, S., Karvonen, M. & Tuomilehto, J. Worldwide increase in incidence of type I diabetes—the analysis of the data on published incidence trends. Diabetologia 42, 1395–1403 (1999).

    CAS  PubMed  Google Scholar 

  6. Diabetes Epidemiology Research International Group. Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes 37, 1113–1119 (1988).

  7. Borchers, A. T., Uibo, R. & Gershwin, M. E. The geoepidemiology of type 1 diabetes. Autoimmun. Rev. 9, A355–A365 (2010).

    PubMed  Google Scholar 

  8. Concannon, P. et al. Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium. Diabetes 58, 1018–1022 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Egeberg, J., Junker, K., Kromann, H. & Nerup, J. Autoimmune insulitis. Pathological findings in experimental animal models and juvenile diabetes mellitus. Acta Endocrinol. Suppl. (Copenh.) 205, 129–137 (1976).

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    CAS  PubMed  Google Scholar 

  12. Lucassen, A. M. et al. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nature Genet. 4, 305–310 (1993).

    CAS  PubMed  Google Scholar 

  13. Barratt, B. J. et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53, 1884–1889 (2004).

    CAS  PubMed  Google Scholar 

  14. Kent, S. C. et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435, 224–228 (2005).

    CAS  PubMed  Google Scholar 

  15. Nakayama, M. et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435, 220–223 (2005). This paper showed the crucial role of insulin in initiating autoimmunity in the NOD mouse model.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004).

    CAS  PubMed  Google Scholar 

  17. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

    CAS  PubMed  Google Scholar 

  18. Vella, A. et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Qu, H. Q., Montpetit, A., Ge, B., Hudson, T. J. & Polychronakos, C. Toward further mapping of the association between the IL2RA locus and type 1 diabetes. Diabetes 56, 1174–1176 (2007).

    CAS  PubMed  Google Scholar 

  20. Smyth, D. J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genet. 38, 617–619 (2006).

    CAS  PubMed  Google Scholar 

  21. Zhernakova, A., van Diemen, C. C. & Wijmenga, C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nature Rev. Genet. 10, 43–55 (2009).

    CAS  PubMed  Google Scholar 

  22. Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).

    CAS  PubMed  Google Scholar 

  23. Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007).

    CAS  PubMed  Google Scholar 

  24. Hakonarson, H. et al. A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes 57, 1143–1146 (2008).

    CAS  PubMed  Google Scholar 

  25. Grant, S. F. et al. Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes 58, 290–295 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genet. 41, 703–707 (2009). This was the largest genome-wide association study and meta-analysis for T1D to date.

    CAS  PubMed  Google Scholar 

  27. Bradfield, J. P. et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet. 7, e1002293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cortes, A. & Brown, M. A. Promise and pitfalls of the Immunochip. Arthritis Res. Ther. 13, 101 (2011).

    PubMed  PubMed Central  Google Scholar 

  30. Howson, J. M., Walker, N. M., Clayton, D., Todd, J. A. & Diabetes Genetics Consortium. Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes. Metab. 11 (Suppl. 1), 31–45 (2009). This paper discusses the highest resolution analysis of T1D susceptibility at the MHC locus, demonstrating that virtually all of the association can be accounted for by HLA classes I and II.

    PubMed  PubMed Central  Google Scholar 

  31. Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887–892 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lowe, C. E. et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nature Genet. 39, 1074–1082 (2007).

    CAS  PubMed  Google Scholar 

  33. Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genet. 37, 1317–1319 (2005).

    CAS  PubMed  Google Scholar 

  34. Fiorillo, E. et al. Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J. Biol. Chem. 285, 26506–518 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Smyth, D. J. et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes 57, 1730–1737 (2008).

    CAS  PubMed  Google Scholar 

  36. Dimas, A. S. et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dixon, A. L. et al. A genome-wide association study of global gene expression. Nature Genet. 39, 1202–1207 (2007).

    CAS  PubMed  Google Scholar 

  38. Melanitou, E., Fain, P. & Eisenbarth, G. S. Genetics of type 1A (immune mediated) diabetes. J. Autoimmun. 21, 93–98 (2003).

    CAS  PubMed  Google Scholar 

  39. Erlich, H. et al. HLA DR–DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57, 1084–1092 (2008). This was the largest and most thorough examination of the HLA class II in T1D.

    CAS  PubMed  Google Scholar 

  40. Todd, J. A., Bell, J. I. & McDevitt, H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987).

    CAS  PubMed  Google Scholar 

  41. Corper, A. L. et al. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288, 505–511 (2000).

    CAS  PubMed  Google Scholar 

  42. Yoshida, K. et al. The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity. J. Clin. Invest. 120, 1578–1590 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wherrett, D. K., Singer, S. M. & McDevitt, H. O. Reduction in diabetes incidence in an I-Ag7 transgenic nonobese diabetic mouse line. Diabetes 46, 1970–1974 (1997). Transgenic overexpression of the diabetogenic I-Ag7 allele protects the non-obese diabetic mouse from diabetes. This paper presents compelling evidence that the alleles at that locus represent loss of function.

    CAS  PubMed  Google Scholar 

  44. Skowera, A. et al. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J. Clin. Invest. 118, 3390–3402 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Velthuis, J. H. et al. Simultaneous detection of circulating autoreactive CD8+ T-cells specific for different islet cell-associated epitopes using combinatorial MHC multimers. Diabetes 59, 1721–1730 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Rotwein, P., Yokoyama, S., Didier, D. K. & Chirgwin, J. M. Genetic analysis of the hypervariable region flanking the human insulin gene. Am. J. Hum. Genet. 39, 291–299 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Vafiadis, P. et al. Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J. Autoimmun. 9, 397–403 (1996).

    CAS  PubMed  Google Scholar 

  48. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, 289–292 (1997). The diabetes-predisposing allele at the insulin locus is associated with reduced expression of insulin in the thymus. This is a report of the first T1D-associated eQTL and one of the first indications that ectopic expression of tissue-specific proteins in the thymus has an important role in self-tolerance.

    CAS  PubMed  Google Scholar 

  49. Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nature Genet. 15, 293–297 (1997).

    CAS  PubMed  Google Scholar 

  50. Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006).

    CAS  PubMed  Google Scholar 

  51. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

    CAS  PubMed  Google Scholar 

  52. Aaltonen, J. et al. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nature Genet. 17, 399–403 (1997).

    Google Scholar 

  53. Chentoufi, A. A. & Polychronakos, C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 51, 1383–1390 (2002).

    CAS  PubMed  Google Scholar 

  54. Faideau, B. et al. Tolerance to proinsulin-2 is due to radioresistant thymic cells. J. Immunol. 177, 53–60 (2006).

    CAS  PubMed  Google Scholar 

  55. Thebault-Baumont, K. et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J. Clin. Invest. 111, 851–857 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Vafiadis, P. et al. Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J. Clin. Endocrinol. Metab. 86, 3705–3710 (2001).

    CAS  PubMed  Google Scholar 

  58. Chin, R. K. et al. Lymphotoxin pathway directs thymic Aire expression. Nature Immunol. 4, 1121–1127 (2003).

    CAS  Google Scholar 

  59. Levi, D. & Polychronakos, C. Regulation of insulin gene expression by cytokines and cell-cell interactions in mouse medullary thymic epithelial cells. Diabetologia 52, 2151–2158 (2009).

    CAS  PubMed  Google Scholar 

  60. Cai, C. Q., Zhang, T., Breslin, M. B., Giraud, M. & Lan, M. S. Both polymorphic variable number of tandem repeats and autoimmune regulator modulate differential expression of insulin in human thymic epithelial cells. Diabetes 60, 336–344 (2011).

    CAS  PubMed  Google Scholar 

  61. Koh, A. S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl Acad. Sci. USA 105, 2878–2883 (2008).

    Google Scholar 

  62. Criswell, L. A. et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–71 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Gregorieff, A., Cloutier, J. F. & Veillette, A. Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50csk. J. Biol. Chem. 273, 13217–13222 (1998).

    CAS  PubMed  Google Scholar 

  64. Orru, V. et al. A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum. Mol. Genet. 18, 569–579 (2009).

    CAS  PubMed  Google Scholar 

  65. Stanford, S. M. et al. Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells. J. Med. Chem. 54, 1640–1654 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Yu, X. et al. Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc. Natl Acad. Sci. USA 104, 19767–19772 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sakaguchi, S. Regulatory T cells: history and perspective. Methods Mol. Biol. 707, 3–17 (2011).

    CAS  PubMed  Google Scholar 

  68. Qu, H. Q. et al. The type I diabetes association of the IL2RA locus. Genes Immun. 10, S42–S48 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Qu, H. Q. et al. A cis-acting regulatory variant in the IL2RA locus. J. Immunol. 183, 5158–5162 (2009).

    CAS  PubMed  Google Scholar 

  70. Dendrou, C. A. et al. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genet. 41, 1011–1015 (2009).

    CAS  PubMed  Google Scholar 

  71. Yamanouchi, J. et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nature Genet. 39, 329–337 (2007).

    CAS  PubMed  Google Scholar 

  72. Anjos, S., Nguyen, A., Ounissi-Benkalha, H., Tessier, M. C. & Polychronakos, C. A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J. Biol. Chem. 277, 46478–46486 (2002).

    CAS  PubMed  Google Scholar 

  73. Anjos, S. M., Shao, W., Marchand, L. & Polychronakos, C. Allelic effects on gene regulation at the autoimmunity-predisposing CTLA4 locus: a re-evaluation of the 3′ +6230G>A polymorphism. Genes Immun. 6, 6305–6311 (2005).

    Google Scholar 

  74. Carpino, N. et al. Regulation of ZAP-70 activation and TCR signalling by two related proteins, Sts-1 and Sts-2. Immunity 20, 37–46 (2004).

    CAS  PubMed  Google Scholar 

  75. Jin, Y. et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N. Engl. J. Med. 362, 1686–1697 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhernakova, A. et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 7, e1002004 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Concannon, P. et al. A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 57, 2858–2861 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Van Goor, J. C., Massa, G. G. & Hirasing, R. Increased incidence and prevalence of diabetes mellitus in Down's syndrome. Arch. Dis. Child. 77, 186 (1997).

    CAS  PubMed  Google Scholar 

  79. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    CAS  PubMed  Google Scholar 

  80. Zouk, H., Marchand, L. & Polychronakos, C. Study of transcriptional effects in cis at the IFIH1 locus. PLoS ONE 5, e11564 (2010).

    PubMed  PubMed Central  Google Scholar 

  81. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009). This paper discusses a prototype for the analysis of low-frequency, high-penetrance variants. A thorough search will require scaling-up by two orders of magnitude.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chistiakov, D. A., Voronova, N. V., Savost'Anov, K. V. & Turakulov, R. I. Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-β production in peripheral blood mononuclear cells of type 1 diabetes patients. Hum. Immunol. 71, 1128–1134 (2010).

    CAS  PubMed  Google Scholar 

  83. Liu, S. et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum. Mol. Genet. 18, 358–365 (2009).

    CAS  PubMed  Google Scholar 

  84. Zouk, H., Marchand, L. & Polychronakos, C. Study of transcriptional effects in cis at the IFIH1 locus. PLoS ONE 5, e11564 (2010).

    PubMed  PubMed Central  Google Scholar 

  85. Heinig, M. et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Schadt, E. E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

    PubMed  PubMed Central  Google Scholar 

  87. Plagnol, V., Smyth, D. J., Todd, J. A. & Clayton, D. G. Statistical independence of the co-localized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13. Biostatistics 10, 327–334 (2009).

    PubMed  Google Scholar 

  88. Clayton, D. G. Prediction and interaction in complex disease genetics: experience in type 1 diabetes. PLoS Genet. 5, e1000540 (2009).

    PubMed  PubMed Central  Google Scholar 

  89. Schmidt, S. et al. Hypermutable non-synonymous sites are under stronger negative selection. PLoS Genet. 4, e1000281 (2008).

    PubMed  PubMed Central  Google Scholar 

  90. Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nature Rev. Genet. 12, 363–376 (2011).

    CAS  PubMed  Google Scholar 

  91. Craddock, N. et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).

    CAS  PubMed  Google Scholar 

  92. Majewski, J., Schwartzentruber, J., Lalonde, E., Montpetit, A. & Jabado, N. What can exome sequencing do for you? J. Med. Genet. 48, 580–589 (2011).

    CAS  PubMed  Google Scholar 

  93. Mehra, N. K. & Kaur, G. Histocompatibility antigen complex of man. Encyclopedia of Life Sciences 15 Dec 2010 (doi:10.1002/9780470015902.a0001234.pub3).

  94. Hughes, A. L. Major histocompatibility complex (MHC) genes: evolution. Encyclopedia of Life Sciences 30 Apr 2008 (doi:10.1002/9780470015902.a0005133.pub2).

  95. Yang, Y. & Santamaria, P. Lessons on autoimmune diabetes from animal models. Clin. Sci. (Lond.) 110, 627–639 (2006).

    CAS  Google Scholar 

  96. Thayer, T. C., Wilson, S. B. & Mathews, C. E. Use of nonobese diabetic mice to understand human type 1 diabetes. Endocrinol. Metab. Clin. North Am. 39, 541–561 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Driver, J. P., Serreze, D. V. & Chen, Y. G. Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease. Semin. Immunopathol. 33, 67–87 (2011).

    CAS  PubMed  Google Scholar 

  98. MacMurray, A. J. et al. Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res. 12, 1029–1039 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

C.P.'s academic activities are supported by the Sessenwein Award from the Montreal Childrens' Hospital Foundation, the US National Institutes of Health (NIH), the Juvenile Diabetes Research Foundation and the Canadian Diabetes Association. Q.L. is the recipient of a post-doctoral fellowship from the Montreal Children's Hospital Research institute.

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  1. Departments of Pediatrics and Human Genetics, McGill University, Montreal, H3H 1P3, Québec, Canada

    Constantin Polychronakos & Quan Li

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BioGPS entry for CLEC16A

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The Gene Ontology

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Glossary

Sibling relative risk

(λS). The probability of a disease in a sibling of a case divided by the prevalence in the general population.

Secular

In this context, seen in the entire population.

Nonsynonymous SNP

(nsSNP). Also referred to as a nonsynonymous single nucleotide variant (nsSNV), this is a nucleotide change that results in an amino acid change.

Linkage disequilibrium

(LD). The property of two linked polymorphic loci whereby the probability of allele A at locus 1 as a function of allele identity (A or B) at locus 2 on the same chromosome is different from that expected from its frequency (that is, the loci provide information about each other). Because of close proximity, few or no recombinations occur between the loci and equilibration of allele frequencies has not occurred.

Minor allele frequency

(MAF). In a biallelic polymorphism, this is the frequency of the less abundant allele.

Conditional regression

An analytical approach by which the contribution of a polymorphism to a genetic association is assessed after accounting for linkage disequilibrium with other associated polymorphisms in the region. In fine mapping, it is used to define the one or more polymorphisms whose association can account for all other known associations in the region.

Expression QTL

(eQTL). A locus at which genetic allelic variation is associated with variation in gene expression.

T cell receptors

(TCRs). Surface molecules through which T cells can recognize a practically unlimited number of antigens, a molecular diversity that is assured by random somatic rearrangement of the exons encoding the TCR in individual T cells.

Peripheral tissues

In immunology, tissues outside the thymus and spleen.

Pre-proinsulin

The protein product of insulin (INS) mRNA. Cleavage of the signal peptide in the endoplasmic reticulum converts it to proinsulin, and digestion by protein convertase 1 removes the C peptide to produce mature insulin.

Alanine scanning mutagenesis

Methodology for probing the important of each amino acid in a protein domain by serially mutating each amino acid to alanine.

Peripheral blood mononuclear cells

(PBMCs). A mixture of T and B lymphocytes and monocytes. T cells are the major component.

Avidity

The strength of cell–cell interactions. It depends on both the affinity of the molecules involved (that is, the T cell receptor (TCR) and the human leukocyte antigen complex) and their abundance in the immunological synapse. Thus, low-affinity TCRs could interact with high avidity in the presence of abundant antigen as, for example, with insulin-specific TCRs in the lymph nodes draining the pancreas in the presence of β-cell death.

Receiver operating characteristic curve

(ROC curve). A graphical plot based on signal detection theory that plots sensitivity along the y axis and 1 – specificity along the x axis for a binary classifier system, such as a genetic test or indeed any clinical test. ROC curve analysis can help select optimal diagnostic models and is fundamental to cost versus benefit analysis of diagnostic decision making.

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Polychronakos, C., Li, Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet 12, 781–792 (2011). https://doi.org/10.1038/nrg3069

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