Genome‐Wide Association Study Identifies Risk Loci for Cluster Headache

Abstract

Objective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome‐wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene‐set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10−17, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10−17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10−8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10−8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome‐wide significant associations supporting a genetic predisposition in cluster headache in a genome‐wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202

No significant association between SNPs in the CLOCK and ADH4 genes and susceptibility to cluster headaches: A systematic review and meta‐analysis

“…These limitations may mask the true influence of candidate polymorphisms in CH, (e.g., CLOCK rs1801260, ADH4 rs1126671 and rs1800759 in this meta-analysis) and emphasized the necessity of conducting further studies on CLOCK and ADH4 polymorphisms to determine their modest genetic effect in CH. The latest GWAS published in June 2021 (O'Connor et al, 2021) compared 852 UK and 591 Swedish CH cases with 5614 and 1134 controls, respectively, and did not find any association between the three SNPs and CH, thus verifying the results of our meta-analysis. Notably, they identified four new susceptibility loci for CH: rs113658130 and rs4519530 on chromosome 2, rs12121134 on chromosome 1 and rs11153082 on chromosome 6, which may provide unprecedented insights for future studies on the pathophysiology of genotype-phenotype associations underlying CH.…”

Cluster Analysis Revealed Two Hidden Phenotypes of Cluster Headache

“…A better understanding of the sources of heterogeneity may lead to more effective treatment strategies according to patient profiles. We think that our approach with cluster analysis will be of help in unraveling underlying genetic mechanisms of CH, which seems to bear some heterogeneity within its clinical phenotype ( 43 , 44 ).…”

Effects of cluster headache preventatives on mouse hypothalamic transcriptional homeostasis

“…Interestingly, Clock and Cry nucleotide polymorphisms segregate with CH patients (9,10). Similarly, genetic susceptibility loci are present in CH patients, even though they do not seem to be specifically related to hypothalamic function regulation (11). Together, these findings corroborate the relevance of specific chronotypes/gene association in CH pathogenesis.…”