A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N = 223,773)

Background: Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. Methods: We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. Results: We identified 3343 SNPs which reached the genome-wide significance level of P < 5 × 10^{− 8}. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 × 10^{− 47}. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 × 10^{− 15} in the LINC02210-CRHR1 gene was the top SNP. Significant relationships between multiple brain tissues and genetic associations were identified through tissue expression analysis. We also identified significant positive genetic correlations between headache and many psychological traits. Conclusions: Our results suggest that brain function is closely related to broadly-defined headache. In addition, we found that many psychological traits have genetic correlations with headache.