Royal College of Surgeons in Ireland
Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.pdf (826.92 kB)

Genome-wide association study identifies risk loci for cluster headache

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journal contribution
posted on 2023-11-17, 17:04 authored by Emer O'Connor, Ciaran Campbell, Gianpiero CavalleriGianpiero Cavalleri, Andrea Carmine Belin

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.


Swedish Research Council (2017-01096)

Swedish Brain Foundation

Mellby Gård Foundation (FO2018-0008)

Karolinska Institutet Research Funds (2018-01738)

Brain Research UK

Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA)

Health Education England

Medical Research Council

Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z)

Swedish Research Council through grant agreement no. 2018-05973



The original article is available at

Published Citation

O'Connor E. et al. Genome-wide association study identifies risk loci for cluster headache. Ann Neurol. 2021;90(2):193-202.

Publication Date

29 June 2021

PubMed ID



  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders




  • Published Version (Version of Record)