Shared genetics and causal relationships between migraine and thyroid function traits.

Abstract

Epidemiological studies have reported a comorbid relationship between migraine and thyroid dysfunction. We investigated the genetic relationship between migraine and thyroid function traits using genome-wide association study (GWAS) data. We found a significant genetic correlation (rg) with migraine for hypothyroidism (rg = 0.0608), secondary hypothyroidism (rg = 0.195), free thyroxine (fT4) (rg = 0.0772), and hyperthyroidism (rg = -0.1046), but not thyroid stimulating hormone (TSH). Pairwise GWAS analysis revealed two shared loci with TSH and 11 shared loci with fT4. Cross-trait GWAS meta-analysis of migraine identified novel genome-wide significant loci: 17 with hypothyroidism, one with hyperthyroidism, five with secondary hypothyroidism, eight with TSH, and 15 with fT4. Of the genes at these loci, six (RERE, TGFB2, APLF, SLC9B1, SGTB, BTBD16; migraine + hypothyroidism), three (GADD45A, PFDN1, RSPH6A; migraine + TSH), and three (SSBP3, BRD3, TEF; migraine + fT4) were significant in our gene-based analysis (pFisher's combined P-value < 2.04 × 10-6). In addition, causal analyses suggested a negative causal relationship between migraine and hyperthyroidism (p = 8.90 × 10-3) and a positive causal relationship between migraine and secondary hypothyroidism (p = 1.30 × 10-3). These findings provide strong evidence for genetic correlation and suggest complex causal relationships between migraine and thyroid traits.