GWAS identifies 7 loci for cluster headache

The International Consortium for Cluster Headache Genetics (CCG) performed a well-powered genome-wide association study (GWAS) in the form of a meta-analysis and identified 7 risk loci for cluster headache, 3 of which are novel. Mendelian randomisation analysis indicated that smoking is a causal factor.

The CCG is a global collaboration to uncover the genetic basis of cluster headache and other rare headache disorders, in which 15 medical institutions currently cooperate (https://www.clusterheadachegenetics.org/). Dr Caroline Ran (Karolinska Institute, Sweden) and colleagues performed a meta-analysis including 4,043 patients with clinically diagnosed cluster headache and 21,729 controls from 9 European countries.

The polygenic basis of cluster headache was confirmed, with a single nucleotide polymorphism (SNP)-based heritability of 14.5%. The analysis identified 7 genome-wide loci for cluster headache. Four of these had been previously identified on chromosomes 1, 2, and 6: DUSP10, rs17011182 (OR 1.38); MERTK, rs13399108 (OR 1.41); FTCDNL1, rs6714578 (OR 1.53); and FHL5, rs9486725 (OR 1.29). Three were novel, on chromosomes 7, 10, and 12: WNT2, rs2402176 (OR 1.20); PLCE1, rs57866767 (OR 1.18); and LRP1, rs11172113 (OR 1.18). There was an overlap with known migraine loci.

Downstream analysis revealed a significant genetic correlation of cluster headache with 84 traits. Among these were risk-taking behaviour, ADHD, depression, and musculoskeletal pain. However, the most significant correlation was with cigarettes smoked per day; 10 of the 84 identified traits were related to smoking. To further dissect this effect, Mendelian randomisation analysis was performed using 40 SNPs previously associated with smoking. Inverse variant-weighted analysis indicated a causal effect of cigarette smoking intensity on cluster headache (P<0.0001). This observation, the authors concluded, may have clinical implications.

 

1. 1. Winsvold BS, et al. Cluster headache genome-wide association study identifies seven loci and implicates smoking as causal risk factor. A5, EHC 2022, 07–10 December, Vienna, Austria.

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Posted on 5 January, 2023