Genetics of Graves' Disease

Abstract

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.