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 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 PTPN22, rs3184504 in SH2B3, and rs2517532 in the HLA class I region (p-values 2.8·10(-13), 2.6·10(-12), and 1.3·10(-8), respectively). We also report associations with rs4915077 near VAV3 (p-value 7.5·10(-10)) and rs925489 near FOXE1 (p value 2.4·10(-19)). VAV3 is involved in immune function, and FOXE1 and PTPN22 have previously been associated with hypothyroidism. Although the HLA class I region and SH2B3 have previously been linked with a number of autoimmune diseases, this is the first report of their association with thyroid disease. The VAV3 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 CAPZB, PDE8B, and CTLA4. CAPZB and PDE8B have been linked to TSH levels and CTLA4 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.

Figure 1. SNPs in the VAV3 region.

In the plot, circles represent unannotated SNPs, upside-down triangles represent non-synonymous variants, and boxes with an “x” are SNPs in regions that are highly conserved across 44 placental mammals. Colors depict the squared correlation () of each SNP with the most associated SNP (i.e., rs4915077, shown in purple). Gray indicates SNPs for which information was missing. Plots were produced using the LocusZoom program .

Figure 2. SNPs in the HLA region.

(A) shows statistics for the main GWAS, (B) shows statistics conditioned on 5 genome-wide significant SNPs (rs925489, rs6679677, rs3184504, rs4915077, rs2517532). For details, see Figure 1.

Figure 3. Summary of results.

Regions associated with hypothyroidism classified by signficance level (genome-wide or suggestive), known function (thyroid versus autoimmune), and whether they had previously been associated with hypothyroidism.