Novel Associations for Hypothyroidism Include Known Autoimmune Risk Loci

Abstract

<div><p>Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the current largest genome-wide association study of hypothyroidism, in 3,736 cases and 35,546 controls. Hypothyroidism was assessed via web-based questionnaires. We identify five genome-wide significant associations, three of which are well known to be involved in a large spectrum of autoimmune diseases: rs6679677 near <em>PTPN22</em>, rs3184504 in <em>SH2B3</em>, and rs2517532 in the HLA class I region (-values , , and , respectively). We also report associations with rs4915077 near <em>VAV3</em> (-value ) and rs925489 near <em>FOXE1</em> (-value ). <em>VAV3</em> is involved in immune function, and <em>FOXE1</em> and <em>PTPN22</em> have previously been associated with hypothyroidism. Although the HLA class I region and <em>SH2B3</em> have previously been linked with a number of autoimmune diseases, this is the first report of their association with thyroid disease. The <em>VAV3</em> association is also novel. We also show suggestive evidence of association for hypothyroidism with a SNP in the HLA class II region (independent of the other HLA association) as well as SNPs in <em>CAPZB</em>, <em>PDE8B</em>, and <em>CTLA4</em>. <em>CAPZB</em> and <em>PDE8B</em> have been linked to TSH levels and <em>CTLA4</em> to a variety of autoimmune diseases. 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 five genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.0.</p> </div