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
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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
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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
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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
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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
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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
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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
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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.
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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
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