Novel associations for hypothyroidism include known autoimmune risk loci

Abstract

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near PTPN22 and rs3184504 in SH2B3 (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near VAV3 (p-value 8.3e-11), another gene involved in immune function, and rs965513 near FOXE1 (p-value 3.1e-14). Of these, the association with PTPN22 confirms a recent small candidate gene study, and FOXE1 was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although SH2B3 has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The VAV3 association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1.