Abstract
AbstractHypothyroidism 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.
Highlights
Hypothyroidism is characterized by deficiencies of thyroid hormones T3 and T4
Hypothyroidism is often marked by high thyroid-stimulating hormone (TSH) levels, which are typically indicative of impaired thyroid function; this is not always the case, e.g., if reduced T3/T4 levels are caused by insufficient generation of TSH by the pituitary gland rather than thyroid dysfunction
We classified as cases individuals who had been diagnosed with hypothyroidism, had elevated TSH levels, or were taking thyroid hormone replacement medication
Summary
Hypothyroidism is characterized by deficiencies of thyroid hormones T3 (triiodothyronine) and T4 (thyroxine). Hypothyroidism is often marked by high thyroid-stimulating hormone (TSH) levels, which are typically indicative of impaired thyroid function; this is not always the case, e.g., if reduced T3/T4 levels are caused by insufficient generation of TSH by the pituitary gland rather than thyroid dysfunction. A second SNP near FOXE1 (rs755109) has been associated with TSH levels in an isolated Pacific Island population [5]. Almost all of these regions contain genes associated with thyroid function: in addition to the thyroid transcription factors, PDE8B is primarily expressed in the thyroid [7] and encodes a phosphodiesterase with a high affinity for cAMP, which mediates TSH effects in the thyroid [8]
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