Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

Emer O'Connor, Carmen Fourier, Caroline Ran, Prasanth Sivakumar, Franziska Liesecke, Laura Southgate, Aster V.E. Harder, Lisanne S. Vijfhuizen, Janice Yip, Nicola Giffin, Nicholas Silver, Fayyaz Ahmed, Isabel C. Hostettler, Brendan Davies, M. Zameel Cader, Benjamin S. Simpson, Roisin Sullivan, Stephanie Efthymiou, Joycee Adebimpe, Olivia QuinnCiaran Campbell, Gianpiero L. Cavalleri, Michail Vikelis, Tim Kelderman, Koen Paemeleire, Emer Kilbride, Lou Grangeon, Susie Lagrata, Daisuke Danno, Richard Trembath, Nicholas W. Wood, Ingrid Kockum, Bendik S. Winsvold, Anna Steinberg, Christina Sjöstrand, Elisabet Waldenlind, Jana Vandrovcova, Henry Houlden*, Manjit Matharu, Andrea Carmine Belin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)193-202
Number of pages10
JournalAnnals of Neurology
Volume90
Issue number2
Early online date14 Jul 2021
DOIs
Publication statusPublished - Aug 2021

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