Genetics of Graves' Disease


Graves' disease (GD) is a common autoimmune condition characterised by autoantibody attack against components of the thyroid gland which leads to hyperthyroidism. Both genetic and environmental factors have been implicated in disease onset. Uncovering the genetic contribution to GD has revealed that the disease is caused by a variety of factors encompassing both immunological and thyroid specific pathways. Recent advancements in genetic screening technologies, including the success of genome‐wide association studies, have provided further insights into GD susceptibility loci. The challenge now is to determine how these newly found susceptibility loci play a role in disease while simultaneously identifying the remainder of the genetic contribution to GD. This will, in turn, piece together the complex pathogenic pathways associated with GD, painting a clearer picture of disease development and with it the provision of new opportunities for improved therapeutics and treatment strategies.

Key Concepts:

  • In Graves' disease (GD) autoantibodies are produced which bind to and constitutively activate the thyroid‐stimulating hormone receptor usually resulting in the overproduction of the thyroid hormones, triiodothyronine and thryoxine.

  • GD is a complex disease caused by a variety of genetic and environmental factors.

  • A variety of different genetic approaches have been used to detect the genetic contribution to GD, including case‐control studies and genome‐wide association scans.

  • GD susceptibility loci are likely to alter both immunological and thyroid specific pathways.

  • Many of the GD susceptibility loci are also found to contribute to other autoimmune diseases suggesting the presence of shared autoimmune disease pathways.

  • Confirmed GD susceptible loci, detected to date, only account for a small amount of the observed genetic effect, with a large degree of genetic heritability still unaccounted for.

  • Fine mapping of known gene effects, screening of low frequency and rare variants and investigating gene–gene and gene–environment interactions are currently being undertaken to locate the remaining missing genetic heritability for GD.

Keywords: Graves' disease; genome‐wide association studies; autoimmunity; genetics; susceptibility loci; human leucocyte antigen; thyroid; case‐control studies; linkage disequilibrium; autoimmune thyroid disease

Figure 1.

How thyroid function is disrupted in Graves’ disease (GD). Diagrammatic representation of how thyroid function and control of thyroid signalling is altered in GD by the production of autoantibodies directed against the thyroid‐stimulating hormone receptor (TSHR). (1) The hypothalamus senses when thyroid hormone levels are low and releases thyrotropin releasing hormone (TRH) which stimulates thyroid‐stimulating hormone (TSH) production in the pituitary gland. (2) TSH binds to the TSHR on thyroid follicular cells. (3) This activates signalling pathways stimulating gene expression. (4) Gene expression leads to the synthesis of thyroglobulin (Tg) which is exocytosed into the follicular lumen. (5) Thyroid peroxidase (TPO) adds iodine to Tg. (6) These chains then conjugate and the Tg is endocytosed back into the thyroid follicular cell. (7) Proteases degrade the protein chain leaving thyroid hormone molecules triiodothyronine (T3) and thyroxine (T4) which are subsequently exocytosed into the bloodstream. Although both are produced by the thyroid, the majority of T3 comes from the conversion of T4 by iodothyronine deiodinases (IYH) in peripheral tissues (shown by the curved arrow). (8) Excess T3 and T4 hormones negatively feedback through inhibition of TRH and as a consequence TSH expression. This reduces TSH production and in turn T3 and T4 production. (9) TSHRAbs which are produced during GD effectively block this negative feedback mechanism by binding to and constitutively activating the receptor, driving forward autonomous T3 and T4 production. High levels of T3 and T4 suppress TSH levels accordingly.

Figure 2.

Timeline of notable GD associated genes. Case‐control studies initially led to the identification of HLA class II region, CTLA‐4 and PTPN22 yet stagnated until the use of Tag SNPs and fluorescent genotyping came in the early 2000s leading to the identification of additional susceptibility loci. GWAS confirmed many of the results from case‐control studies while also identifying other potential modulators of GD. Δ denotes gene found in region identified through linkage studies and confirmed by case‐control studies. * denotes gene originally found in case‐control studies and confirmed by GWAS.

Figure 3.

Inhibition at the immunological synapse. HLA class II molecules on the surface of antigen‐presenting cells (APCs) interact with the T cell receptor (TCR) of the CD4+ Th cells. If the TCR recognises the antigen as nonself, a primary signal is transduced. A secondary signal is then required via CD80/CD86 coreceptors on the APC interacting with CD28 on the T cell. CTLA‐4 acts to inhibit this second signal via binding to CD80/CD86 preventing CD28 signal transduction. CTLA‐4 is also proposed to directly inhibit the TCR or inhibit other signalling molecules including ITAM kinases, Fyn, Lck and Zap‐70. CTLA‐4 could also interact with the LYP–Grb2 complex to inhibit T cell activation by a currently unknown mechanism. LYP interacts with further adaptor molecules involved in controlling downstream T cell signalling including Csk and c‐Cbl. The LYP–Csk complex associates with the Fyn and Lck kinases, allowing LYP to dephosphorylate and inactivate the kinases. The LYP–c‐Cbl complex also inhibits T cell signalling through dephosphorylation of Zap‐70 while it interacts with the ITAM domains of the TCR (Brand et al., ).



Ban Y , Davies TF , Greenberg DA et al. (2004) Arginine at position 74 of the HLA‐DR beta1 chain is associated with Graves' disease. Genes and Immunity 5(3): 203–208.

Ban Y , Greenberg DA , Concepcion E et al. (2003) Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proceedings of the National Academy of Sciences of the USA 100(25): 15119–15124.

Barrett JC , Clayton DG , Concannon P et al. (2009) Genome‐wide association study and meta‐analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genetics 41(6): 703–707.

Brand O , Gough S and Heward J (2005) HLA, CTLA‐4 and PTPN22: the shared genetic master‐key to autoimmunity? Expert Reviews in Molecular Medicine 7(23): 1–15.

Brand OJ , Barrett JC , Simmonds MJ et al. (2009) Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Human Molecular Genetics 18(9): 1704–1713.

Brand OJ and Gough SC (2010) Genetics of thyroid autoimmunity and the role of the TSHR. Molecular and Cellular Endocrinology 322(1‐2): 135–143.

Brand OJ , Lowe CE , Heward JM et al. (2007) Association of the interleukin‐2 receptor alpha (IL‐2Ralpha)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs. Clinical Endocrinology 66(4): 508–512.

Brix TH , Christensen K , Holm NV et al. (1998) A population‐based study of Graves' disease in Danish twins. Clinical Endocrinology 48(4): 397–400.

Brix TH , Knudsen GP , Kristiansen M et al. (2005) High frequency of skewed X‐chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. Journal of Clinical Endocrinology and Metabolism 90(11): 5949–5953.

Brix TH , Kyvik KO , Christensen K and Hegedus L (2001) Evidence for a major role of heredity in Graves' disease: a population‐based study of two Danish twin cohorts. Journal of Clinical Endocrinology and Metabolism 86(2): 930–934.

Brucker‐Davis F (1998) Effects of environmental synthetic chemicals on thyroid function. Thyroid 8(9): 827–856.

Burton PR , Clayton DG , Cardon LR et al. (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genetics 39(11): 1329–1337.

Chabchoub G , Uz E , Maalej A et al. (2009) Analysis of skewed X‐chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases. Arthritis Research and Therapy 11(4): R106.

Chistiakov DA , Chistiakova EI , Voronova NV , Turakulov RI and Savost'anov KV (2011) A variant of the Il2ra/Cd25 gene predisposing to graves' disease is associated with increased levels of soluble interleukin‐2 receptor. Scandinavian Journal of Immunology 74(5): 496–501.

Chu X , Pan CM , Zhao SX et al. (2011) A genome‐wide association study identifies two new risk loci for Graves' disease. Nature Genetics 43(9): 897–901.

Collins JE , Heward JM , Howson JM et al. (2004) Common allelic variants of exons 10, 12, and 33 of the thyroglobulin gene are not associated with autoimmune thyroid disease in the United Kingdom. Journal of Clinical Endocrinology and Metabolism 89(12): 6336–6339.

Cooper JD , Simmonds MJ , Walker NM et al. (2012) Seven newly identified loci for autoimmune thyroid disease. Human Molecular Genetics 21(23): 5202–5208.

Craddock N , Hurles ME , Cardin N et al. (2010) Genome‐wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464(7289): 713–720.

Gough SC and Simmonds MJ (2007) The HLA region and autoimmune disease: associations and mechanisms of action. Current Genomics 8(7): 453–465.

Gough SC , Walker LS and Sansom DM (2005) CTLA4 gene polymorphism and autoimmunity. Immunogical Reviews 204: 102–115.

Hegedius L , Brix TH and Vestergaard P (2004) Relationship between cigarette smoking and Graves' ophthalmopathy. Journal of Endocrinological Investigation 27(3): 265–271.

Hemminki K , Li X , Sundquist J and Sundquist K (2010) The epidemiology of Graves' disease: evidence of a genetic and an environmental contribution. Journal of Autoimmunity 34(3): J307–J313.

Hiratani H , Bowden DW , Ikegami S et al. (2005) Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves' disease. Journal of Clinical Endocrinology and Metabolism 90(5): 2898–2903.

Hunt KA , Mistry V , Bockett NA et al. (2013) Negligible impact on missing heritability of autoimmune‐locus rare coding‐region variants. Nature 498(7453): 232–235.

Kallies A and Nutt SL (2010) Bach2: plasma‐cell differentiation takes a break. EMBO Journal 29(23): 3896–3897.

Kochi Y , Myouzen K , Yamada R et al. (2009) FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B‐cell receptor‐mediated signaling. Journal of Immunology 183(9): 5502–5510.

Kochi Y , Yamada R , Suzuki A et al. (2005) A functional variant in FCRL3, encoding Fc receptor‐like 3, is associated with rheumatoid arthritis and several autoimmunities. Nature Genetics 37(5): 478–485.

Laurberg P , Pedersen KM , Hreidarsson A et al. (1998) Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. Journal of Clinical Endocrinology and Metabolism 83(3): 765–769.

Lazarus JH (2012) Epidemiology of Graves' orbitopathy (GO) and relationship with thyroid disease. Best Practice and Research Clinical Endocrinology and Metabolism 26(3): 273–279.

Maier LM , Anderson DE , Severson CA et al. (2009) Soluble IL‐2RA levels in multiple sclerosis subjects and the effect of soluble IL‐2RA on immune responses. Journal of Immunology 182(3): 1541–1547.

Muto A , Tashiro S , Nakajima O et al. (2004) The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429(6991): 566–571.

Nejentsev S , Walker N , Riches D , Egholm M and Todd JA (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324(5925): 387–389.

Ozcelik T , Uz E , Akyerli CB et al. (2006) Evidence from autoimmune thyroiditis of skewed X‐chromosome inactivation in female predisposition to autoimmunity. European Journal of Human Genetics 14(6): 791–797.

Ploski R , Brand OJ , Jurecka‐Lubieniecka B et al. (2010) Thyroid stimulating hormone receptor (TSHR) intron 1 variants are major risk factors for Graves' disease in three European Caucasian cohorts. PLOS One 5(11): e15512.

Prummel MF , Strieder T and Wiersinga WM (2004) The environment and autoimmune thyroid diseases. European Journal of Endocrinology 150(5): 605–618.

Saravanan P and Dayan CM (2001) Thyroid autoantibodies. Endocrinology and Metabolism Clinics of North America 30(2): 315–337, viii.

Simmonds MJ (2013) GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis. Nature Reviews Endocrinology 9(5): 277–287.

Simmonds MJ , Heward JM , Carr‐Smith J et al. (2006) Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease. Journal of Clinical Endocrinology and Metabolism 91(3): 1056–1061.

Simmonds MJ , Howson JM , Heward JM et al. (2005) Regression mapping of association between the human leukocyte antigen region and Graves disease. American Journal of Human Genetics 76(1): 157–163.

Simmonds MJ , Howson JM , Heward JM et al. (2007) A novel and major association of HLA‐C in Graves' disease that eclipses the classical HLA‐DRB1 effect. Human Molecular Genetics 16(18): 2149–2153.

Simmonds MJ , Yesmin K , Newby PR et al. (2010) Confirmation of association of chromosome 5q31‐33 with United Kingdom Caucasian Graves' disease. Thyroid 20(4): 413–417.

Smyth D , Cooper JD , Collins JE et al. (2004) 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(11): 3020–3023.

Song HD , Liang J , Shi JY et al. (2009) Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease. Human Molecular Genetics 18(6): 1156–1170.

Szymanski K , Bednarczuk T , Krajewski P et al. (2012) The replication of the association of the rs6832151 within chromosomal band 4p14 with Graves' disease in a Polish Caucasian population. Tissue Antigens 79(5): 380–383.

Todd JA , Walker NM , Cooper JD et al. (2007) Robust associations of four new chromosome regions from genome‐wide analyses of type 1 diabetes. Nature Genetics 39(7): 857–864.

Ueda H , Howson JM , Esposito L et al. (2003) Association of the T‐cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423(6939): 506–511.

Velaga MR , Wilson V , Jennings CE et al. (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. Journal of Clinical Endocrinology and Metabolism 89(11): 5862–5865.

Wellcome Trust Case Control Consortium, Maller JB , McVean G et al. (2012) Bayesian refinement of association signals for 14 loci in 3 common diseases. Nature Genetics 44(12): 1294–1301.

Yin X , Latif R , Tomer Y and Davies TF (2007) Thyroid epigenetics: X chromosome inactivation in patients with autoimmune thyroid disease. Annals of the New York Academy of Sciences 1110: 193–200.

Further Reading

Boelaert K , Newby PR , Simmonds MJ et al. (2010) Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. American Journal of Medicine 123(2): 183 e181–183 e189.

Eichler EE , Flint J , Gibson G et al. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nature Reviews Genetics 11(6): 446–450.

Gregersen PK and Behrens TW (2006) Genetics of autoimmune diseases – disorders of immune homeostasis. Nature Reviews Genetics 7(12): 917–928.

Manolio TA , Collins FS , Cox NJ et al. (2009) Finding the missing heritability of complex diseases. Nature 461(7265): 747–753.

Nakamura Y (2009) DNA variations in human and medical genetics: 25 years of my experience. Journal of Human Genetics 54(1): 1–8.

Simmonds MJ (2011) Evaluating the role of B Cells in autoimmune disease: more than just initiators of disease? In: Berhardt LV (ed.) Advances in Medicine and Biology, vol. 28, pp 151–176. New York: Nova Science Publisher, Inc.

Simmonds MJ and Gough SC (2011) The search for the genetic contribution to autoimmune thyroid disease: the never ending story? Briefings in Functional Genomics 10(2): 77–90.

Simmonds MJ and Gough SCL (2011) Endocrine autoimmunity. In: Wass JAH and Stewart PM (eds) Oxford Textbook of Endocrinology and Diabetes, pp 34–44. Oxford: Oxford University Press.

Tomer Y and Davies TF (1993) Infection, thyroid disease, and autoimmunity. Endocrine Reviews 14(1): 107–120.

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Hamilton, Alexander, Gough, Stephen CL, and Simmonds, Matthew J(Sep 2013) Genetics of Graves' Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024977]