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.

  • Review Article
  • Published:

GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis

Abstract

The ability of the immune system to protect the body from attack by foreign antigens is essential for human survival. The immune system can, however, start to attack the body's own organs. An autoimmune response against components of the thyroid gland affects 2–5% of the general population. Considerable familial clustering is also observed in autoimmune thyroid disease (AITD). Teasing out the genetic contribution to AITD over the past 40 years has helped unravel how immune disruption leads to disease onset. Breakthroughs in genome-wide association studies (GWAS) in the past decade have facilitated screening of a greater proportion of the genome, leading to the identification of a before unimaginable number of AITD susceptibility loci. This Review will focus on the new susceptibility loci identified by GWAS, what insights these loci provide about the pathogenesis of AITD and how genetic susceptibility loci shared between different autoimmune diseases could help explain disease co-clustering within individuals and families. This Review also discusses where future efforts should be focused to translate this step forward in our understanding of the genetic contribution to AITD into a better understanding of disease presentation and progression, and improved therapeutic options.

Key Points

  • Case–control studies detected several autoimmune thyroid disease (AITD) susceptibility loci; however, difficulties in choosing which genes to screen next affected their effectiveness as a gene discovery tool

  • Genome-wide association studies (GWAS) revolutionized the field of AITD genetics by enabling the detection of several new susceptibility loci, including the HLA class I region, FCRL3, chromosome 6p27, chromosome 4q14 and TSHR

  • Examination of susceptibility loci from related diseases in AITD revealed additional susceptibility loci and supported co-clustering of rheumatoid arthritis and type 1 diabetes mellitus with AITD

  • Susceptibility loci identified by GWAS support a role for viral triggering of disease, disrupted T-cell and B-cell signalling and activation, and thyroid-specific disease pathways in AITD onset and progression

  • GWAS have shown that common genetic variation accounts for a small proportion of the genetic contribution to AITD, and screening additional genetic variation is required to locate missing heritability

  • Understanding the role of known susceptibility loci and determining missing heritability in AITD will provide insights into disease pathogenesis and opportunities to translate these findings into improved therapeutic options

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Use of different techniques over time to identify autoimmune thyroid disease susceptibility loci.
Figure 2: Co-clustering of autoimmune diseases other than autoimmune thyroid disease in white UK patients with Graves disease or Hashimoto thyroiditis.
Figure 3: Role of molecules encoded by known AITD susceptibility loci in T-cell central tolerance and immune monitoring by T cells.

Similar content being viewed by others

References

  1. Tunbridge, W. M. et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. (Oxf.) 7, 481–493 (1977).

    Article  CAS  Google Scholar 

  2. Brix, T. H., Christensen, K., Holm, N. V., Harvald, B. & Hegedüs, L. A population-based study of Graves' disease in Danish twins. Clin. Endocrinol. (Oxf.) 48, 397–400 (1998).

    Article  CAS  Google Scholar 

  3. Brix, T. H., Kyvik, K. O. & Hegedus, L. What is the evidence of genetic factors in the etiology of Graves' disease? A brief review. Thyroid 8, 627–634 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Brix, T. H., Kyvik, K. O., Christensen, K. & Hegedüs, L. Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts. J. Clin. Endocrinol. Metab. 86, 930–934 (2001).

    CAS  PubMed  Google Scholar 

  5. Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: Associations and mechanisms of action. Curr. Genomics 8, 453–465 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Allen, E. M., Appel, M. C. & Braverman, L. E. The effect of iodide ingestion on the development of spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat. Endocrinology 118, 1977–1981 (1986).

    Article  CAS  PubMed  Google Scholar 

  7. Brucker-Davis, F. Effects of environmental synthetic chemicals on thyroid function. Thyroid 8, 827–856 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. McIver, B. & Morris, J. C. The pathogenesis of Graves' disease. Endocrinol. Metab. Clin. North Am. 27, 73–89 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. McAllister-Sistilli, C. G. et al. The effects of nicotine on the immune system. Psychoneuroendocrinology 23, 175–187 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Rosch, P. J. Stressful life events and Graves' disease. Lancet 342, 566–567 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Paunkovic, N., Paunkovic, J., Pavlovic, O. & Paunovic, Z. The significant increase in incidence of Graves' disease in eastern Serbia during the civil war in the former Yugoslavia (1992 to 1995). Thyroid 8, 37–41 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Fricchione, G. L. & Stefano, G. B. The stress response and autoimmunoregulation. Adv. Neuroimmunol. 4, 13–27 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Simmonds, M. J. & Gough, S. C. The search for the genetic contribution to autoimmune thyroid disease: the never ending story? Brief. Funct. Genomics 10, 77–90 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Sakai, K. et al. Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto's thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. Hum. Mol. Genet. 10, 1379–1386 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Tomer, Y., Barbesino, G., Greenberg, D. A., Concepcion, E. & Davies, T. F. Mapping the major susceptibility loci for familial Graves' and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions. J. Clin. Endocrinol. Metab. 84, 4656–4664 (1999).

    CAS  PubMed  Google Scholar 

  16. Tomer, Y. et al. Common and unique susceptibility loci in Graves and Hashimoto diseases: results of whole-genome screening in a data set of 102 multiplex families. Am. J. Hum. Genet. 73, 736–747 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Imrie, H. et al. Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population. J. Clin. Endocrinol. Metab. 86, 626–630 (2001).

    CAS  PubMed  Google Scholar 

  18. Taylor, J. C. et al. A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 91, 646–653 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Vaidya, B. et al. Evidence for a new Graves disease susceptibility locus at chromosome 18q21. Am. J. Hum. Genet. 66, 1710–1714 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Furugaki, K. et al. Association of the T-cell regulatory gene CTLA4 with Graves' disease and autoimmune thyroid disease in the Japanese. J. Hum. Genet. 49, 166–168 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Vaidya, B. et al. The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus. Hum. Mol. Genet. 8, 1195–1199 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Yanagawa, T., Hidaka, Y., Guimaraes, V., Soliman, M. & DeGroot, L. J. CTLA-4 gene polymorphism associated with Graves' disease in a Caucasian population. J. Clin. Endocrinol. Metab. 80, 41–45 (1995).

    CAS  PubMed  Google Scholar 

  24. Smyth, D. et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53, 3020–3023 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Velaga, M. R. et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J. Clin. Endocrinol. Metab. 89, 5862–5865 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  28. The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  29. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Brand, O. J. et al. Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs. Clin. Endocrinol. (Oxf.) 66, 508–512 (2007).

    CAS  Google Scholar 

  31. Simmonds, M. J. et al. A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect. Hum. Mol. Genet. 16, 2149–2153 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Kochi, Y. et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat. Genet. 37, 478–485 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Simmonds, M. J. et al. Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease. J. Clin. Endocrinol. Metab. 91, 1056–1061 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Owen, C. J. et al. Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders suggests a complex pattern of disease association. J. Clin. Endocrinol. Metab. 92, 1106–1111 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Brand, O. J. et al. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease (GD). Hum. Mol. Genet. 18, 1704–1713 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Dechairo, B. M. et al. Association of the TSHR gene with Graves' disease: the first disease specific locus. Eur. J. Hum. Genet. 13, 1223–1230 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Hiratani, H. et al. Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves' disease. J. Clin. Endocrinol. Metab. 90, 2898–2903 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Manolio, T. A. & Collins, F. S. The HapMap and genome-wide association studies in diagnosis and therapy. Annu. Rev. Med. 60, 443–456 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Collins, F. S., Guyer, M. S. & Charkravarti, A. Variations on a theme: cataloging human DNA sequence variation. Science 278, 1580–1581 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Barrett, J. C. & Cardon, L. R. Evaluating coverage of genome-wide association studies. Nat. Genet. 38, 659–662 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Pe'er, I. et al. Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat. Genet. 38, 663–667 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Nakamura, Y. DNA variations in human and medical genetics: 25 years of my experience. J. Hum. Genet. 54, 1–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  44. Chu, X. et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat. Genet. 43, 897–901 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. WTCCC & TACS. Association study of 14,500 nsSNPs in four common diseases identifies variants involved in autoimmunity. Nat. Genet. 39, 1329–1337 (2007).

  46. Simmonds, M. J. et al. Association of Fc receptor-like 5 (FCRL5) with Graves' disease is secondary to the effect of FCRL3. Clin. Endocrinol. (Oxf.) 73, 654–660 (2010).

    Article  CAS  Google Scholar 

  47. Newby, P. R. et al. Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study. Eur. J. Hum. Genet. 18, 1021–1026 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Denny, J. C. et al. Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. Am. J. Hum. Genet. 89, 529–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Eriksson, N. et al. Novel associations for hypothyroidism include known autoimmune risk loci. PLoS ONE 7, e34442 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Barker, J. M. Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J. Clin. Endocrinol. Metab. 91, 1210–1217 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Tait, K. F. et al. Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository. Diabet. Med. 21, 358–362 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Laberge, G. et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 18, 300–305 (2005).

    Article  PubMed  Google Scholar 

  53. Kasperlik-Zaluska, A., Czarnocka, B. & Czech, W. High prevalence of thyroid autoimmunity in idiopathic Addison's disease. Autoimmunity 18, 213–216 (1994).

    Article  CAS  PubMed  Google Scholar 

  54. Barcellos, L. F. et al. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Lancet Neurol. 5, 924–931 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Broadley, S. A., Deans, J., Sawcer, S. J., Clayton, D. & Compston, D. A. Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey. Brain 123, 1102–1111 (2000).

    Article  PubMed  Google Scholar 

  56. Jenkins, R. C. & Weetman, A. P. Disease associations with autoimmune thyroid disease. Thyroid 12, 977–988 (2002).

    Article  PubMed  Google Scholar 

  57. Boelaert, K. et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am. J. Med. 123, 183 e1–e9 (2010).

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Trynka, G. et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193–1201 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cooper, J. D. et al. Seven newly identified loci for autoimmune thyroid disease. Hum. Mol. Genet. 21, 5202–5208 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Simmonds, M. J. & Gough, S. C. L. in Oxford Textbook of Endocrinology and Diabetes (eds Wass, J. A. H. & Stewart, P. M.) 34–44 (Oxford University Press, Oxford, 2012).

    Google Scholar 

  62. Möller, E. Mechanisms for induction of autoimmunity in humans. Acta Paediatr. Suppl. 424, 16–20 (1998).

    PubMed  Google Scholar 

  63. Bowness, P. HLA B27 in health and disease: a double-edged sword? Rheumatology (Oxford) 41, 857–868 (2002).

    Article  CAS  Google Scholar 

  64. Suzuki, K. et al. Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. Proc. Natl Acad. Sci. USA 96, 2285–2290 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McDonald, J. C. & Adamashvili, I. Soluble HLA: a review of the literature. Hum. Immunol. 59, 387–403 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Tabayoyong, W. B. & Zavazava, N. Soluble HLA revisited. Leuk. Res. 31, 121–125 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. Acquati, F. et al. Tumor and metastasis suppression by the human RNASET2 gene. Int. J. Oncol. 26, 1159–1168 (2005).

    CAS  PubMed  Google Scholar 

  69. Liu, J. et al. Chromosome 6 encoded RNaseT2 protein is a cell growth regulator. J. Cell. Mol. Med. 14, 1146–1155 (2010).

    PubMed  Google Scholar 

  70. Monti, L. et al. RNASET2 as a tumor antagonizing gene in a melanoma cancer model. Oncol. Res. 17, 69–74 (2008).

    Article  PubMed  Google Scholar 

  71. Yanaba, K. et al. B-lymphocyte contributions to human autoimmune disease. Immunol. Rev. 223, 284–299 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Simmonds, M. J. in Advances in Medicine and Biology (ed. Berhardt, L. V.) 151–176 (Nova Science Publsiher, Inc., New York, 2011).

    Google Scholar 

  73. Sanz, I., Anolik, J. H. & Looney, R. J. B cell depletion therapy in autoimmune diseases. Front. Biosci. 12, 2546–2567 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Lund, F. E. Cytokine-producing B lymphocytes-key regulators of immunity. Curr. Opin. Immunol. 20, 332–338 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Polson, A. G. et al. Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia. Int. Immunol. 18, 1363–1373 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Davis, R. S. Fc receptor-like molecules. Annu. Rev. Immunol. 25, 525–560 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Ehrhardt, G. R. et al. Fc receptor-like proteins (FCRL): immunomodulators of B cell function. Adv. Exp. Med. Biol. 596, 155–162 (2007).

    Article  PubMed  Google Scholar 

  78. Muto, A. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566–571 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Sasaki, S. et al. Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15. Oncogene 19, 3739–3749 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Muto, A. et al. Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3′ enhancer. EMBO J. 17, 5734–5743 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Castanet, M. & Polak, M. Spectrum of human FOXE1/TTF2 mutations. Horm. Res. Paediatr. 73, 423–429 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. De Felice, M. et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat. Genet. 19, 395–398 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Zannini, M. et al. TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J. 16, 3185–3197 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ortiz, L., Aza-Blanc, P., Zannini, M., Cato, A. C. & Santisteban, P. The interaction between the forkhead thyroid transcription factor TTF-2 and the constitutive factor CTF/NF-1 is required for efficient hormonal regulation of the thyroperoxidase gene transcription. J. Biol. Chem. 274, 15213–15221 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Sirota, M., Schaub, M. A., Batzoglou, S., Robinson, W. H. & Butte, A. J. Autoimmune disease classification by inverse association with SNP alleles. PLoS Genetics 5, e1000792 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cárdenas Roldán, J. et al. Autoimmune thyroid disease in rheumatoid arthritis: a global perspective. Arthritis 2012, 864907 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liao, K. P. et al. Autoantibodies, autoimmune risk alleles and clinical associations in rheumatoid arthritis cases and non-RA controls in the electronic medical records. Arthritis Rheum. (2012).

  89. Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Maller, J. B. et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Huber, A. K. et al. Analysis of immune regulatory genes' copy number variants in Graves' disease. Thyroid 21, 69–74 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cirulli, E. T. & Goldstein, D. B. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat. Rev. Genet. 11, 415–425 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Manji, N. et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J. Clin. Endocrinol. Metab. 91, 4873–4880 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Epstein, D. J. Cis-regulatory mutations in human disease. Brief. Funct. Genomic Proteomic. 8, 310–316 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hodge, S. E. et al. Possible interaction between HLA-DRbeta1 and thyroglobulin variants in Graves' disease. Thyroid 16, 351–355 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Kong, A. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nadeau, J. H. Transgenerational genetic effects on phenotypic variation and disease risk. Hum. Mol. Genet. 18, R202–R210 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vang, T. et al. Protein tyrosine phosphatases in autoimmunity. Annu. Rev. Immunol. 26, 29–55 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Bottini, N., Vang, T., Cucca, F. & Mustelin, T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin. Immunol. 18, 207–213 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Walker, L. S. & Sansom, D. M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 11, 852–863 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Gough, S. C., Walker, L. S. & Sansom, D. M. CTLA4 gene polymorphism and autoimmunity. Immunol. Rev. 204, 102–115 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  107. Brand, O. J. & Gough, S. C. Genetics of thyroid autoimmunity and the role of the TSHR. Mol. Cell Endocrinol. 322, 135–143 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Danoy, P. et al. Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population. Ann. Rheum. Dis. 70, 1793–1797 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Kiss-Toth, E. et al. Human tribbles, a protein family controlling mitogen-activated protein kinase cascades. J. Biol. Chem. 279, 42703–42708 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Wilkin, F. et al. Characterization of a phosphoprotein whose mRNA is regulated by the mitogenic pathways in dog thyroid cells. Eur. J. Biochem. 248, 660–668 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Schoenmakers, E. F. et al. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat. Genet. 10, 436–444 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Bassuk, A. G. et al. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am. J. Hum. Genet. 83, 572–581 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bosoi, C. M. et al. Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects. Hum. Mutat. 32, 1371–1375 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pierce, M. W., Remold-O'Donnell, E., Todd, R. F. 3rd & Arnaout, M. A. N-terminal sequence of human leukocyte glycoprotein Mo1: conservation across species and homology to platelet IIb/IIIa. Biochim. Biophys. Acta 874, 368–371 (1986).

    Article  CAS  PubMed  Google Scholar 

  115. Simon, D. I. et al. Decreased neointimal formation in Mac-1(−/−) mice reveals a role for inflammation in vascular repair after angioplasty. J. Clin. Invest. 105, 293–300 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks S. C. L. Gough, C. U. Onyimba and A. Hamilton for their helpful discussion and advice regarding the writing of this manuscript.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simmonds, M. GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis. Nat Rev Endocrinol 9, 277–287 (2013). https://doi.org/10.1038/nrendo.2013.56

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2013.56

This article is cited by

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