Cross-Trait Genetic Analyses Indicate Pleiotropy and Complex Causal Relationships between Headache and Thyroid Function Traits.

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 ( r g ) with headache and hypothyroidism ( r g = 0.09, p = 2.00 × 10 -4 ), free thyroxine (fT4) ( r g = 0.08, p = 5.50 × 10 -3 ), and hyperthyroidism ( r g = -0.14, p = 1.80 × 10 -3 ), a near significant genetic correlation with secondary hypothyroidism ( r g = 0.20, p = 5.24 × 10 -2 ), 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 ( FAF1 , TMX2-CTNND1 , AARSD1 , PLCD3 , ZNF652 , and C20orf203 ; headache-TSH) and six ( HMGB1P45 , RPL30P1 , ZNF462 , TMX2-CTNND1 , ITPK1 , SECISBP2L ; headache-fT4) were significant in our gene-based analysis ( p Fisher's combined p -value < 2.09 × 10 -6 ). Our causal analysis suggested a positive causal relationship between headache and secondary hypothyroidism ( p = 3.64 × 10 -4 ). The results also suggest a positive causal relationship between hypothyroidism and headache ( p = 2.45 × 10 -3 ) and a negative causal relationship between hyperthyroidism and headache ( p = 1.16 × 10 -13 ). These findings suggest a strong evidence base for a genetic correlation and complex causal relationships between headache and thyroid traits.