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

WINSVOLD, B; CHALMER, MA; BELIN, C; HANSEN, TF; RAN, C; FERKINGSTAD, E; VAN DEN MAAGDENBERG, AMJM; ZWART, JA; HARDER, AV; DALMASSO, MC; MATHARU, M; RAMIREZ, A

Viena

Congreso; 16th European Headache Congress; 2022

Introduction: Cluster headache is a severe primary headache disorder preferentially affecting men. A high proportion of patients are smokers. Objective: Meta-analyzing different European cluster headache cohorts to identifying common genetic variants that confer genetic risk for cluster headache.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 ancestryResults: 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 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.