Cluster headache genome-wide association study identifies seven loci and implicates smoking as causal risk factor

Abstract text (incl. figure legends and references)

Introduction: Cluster headache is a severe primary headache disorder preferentially affecting men. A high proportion of patients are smokers.

Methods: We performed a genome-wide association meta-analysis of 4,043 patients with clinically diagnosed cluster headache and 21,729 controls from ten cohorts of European ancestry.

Results: We confirmed the polygenic basis of cluster headache with a SNP-based heritability of 14.5%. We identified seven genome-wide significant loci, of which three are novel (WNT2, rs2402176, OR = 1.20; PLCE1, rs57866767, OR = 1.18; and LRP1, rs11172113, OR = 1.18) and four previously identified (DUSP10, rs17011182, OR = 1.38; MERTK, rs13399108, OR = 1.41; FTCDNL1, rs6714578, OR = 1.53; and FHL5, rs9486725, OR = 1.29). The prioritized genes showed enrichment for artery and brain tissue. Cluster headache shared only some genetic risk loci with migraine and is genetically correlated with cigarette smoking, risk-taking behavior, ADHD, depression and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache.

Conclusion: We identify seven risk loci, of which three are novel. We provide evidence that cluster headache and migraine have a partly distinct and a partly overlapping genetic basis. Mendelian randomization analysis indicates a causal effect of cigarette smoking on the development of cluster headache, which has potential clinical implications.