Papers of the Week

Epidemiological studies have reported a comorbid relationship between headache and thyroid traits; however, little is known about the shared genetics and causality that contributes to this association. We investigated the genetic overlap and associations between headache and thyroid function traits using genome-wide association study (GWAS) data. We found a significant genetic correlation () with headache and hypothyroidism ( = 0.09, = 2.00 × 10), free thyroxine (fT4) ( = 0.08, = 5.50 × 10), and hyperthyroidism ( = -0.14, = 1.80 × 10), a near significant genetic correlation with secondary hypothyroidism ( = 0.20, = 5.24 × 10), but not with thyroid stimulating hormone (TSH). Pairwise-GWAS analysis revealed six, 14, four and five shared (pleiotropic) loci with headache and hypothyroidism, hyperthyroidism, secondary hypothyroidism, and fT4, respectively. Cross-trait GWAS meta-analysis identified novel genome-wide significant loci for headache: five with hypothyroidism, three with secondary hypothyroidism, 12 with TSH, and nine with fT4. Of the genes at these loci, six (, , , , , and ; headache-TSH) and six (, , , , , ; headache-fT4) were significant in our gene-based analysis ( < 2.09 × 10). Our causal analysis suggested a positive causal relationship between headache and secondary hypothyroidism ( = 3.64 × 10). The results also suggest a positive causal relationship between hypothyroidism and headache ( = 2.45 × 10) and a negative causal relationship between hyperthyroidism and headache ( = 1.16 × 10). These findings suggest a strong evidence base for a genetic correlation and complex causal relationships between headache and thyroid traits.