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Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

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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 Quinn & 20 more Ciaran 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

Original languageEnglish
Pages (from-to)193-202
Number of pages10
JournalAnnals of Neurology
Volume90
Issue number2
Early online date14 Jul 2021
DOIs
Accepted/In press2021
E-pub ahead of print14 Jul 2021
PublishedAug 2021

Bibliographical note

Funding Information: Sweden: This study was supported by the Swedish Research Council (2017-01096), the Swedish Brain Foundation, and the Mellby G?rd Foundation (FO2018-0008), Karolinska Institutet Research Funds (2018-01738). We thank F. Xiang for excellent technical assistance and A.-C. Karlsson for help with patient recruitment. UK: E.O. is supported by Brain Research UK. Patients were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). J.V. is supported by Health Education England and the Medical Research Council. L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George's, University of London. We thank Dr. J. E. Burns for his assistance in preparing the manuscript. The data handling was enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax, Uppsala University partially funded by the Swedish Research Council through grant agreement no. 2018-05973. [Correction added on July 26, 2021 after first online publication: The Acknowledgments section has been updated.] Funding Information: Sweden: This study was supported by the Swedish Research Council (2017‐01096), the Swedish Brain Foundation, and the Mellby Gård Foundation (FO2018‐0008), Karolinska Institutet Research Funds (2018‐01738). We thank F. Xiang for excellent technical assistance and A.‐C. Karlsson for help with patient recruitment. UK: E.O. is supported by Brain Research UK. Patients were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). J.V. is supported by Health Education England and the Medical Research Council. L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George's, University of London. We thank Dr. J. E. Burns for his assistance in preparing the manuscript. Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

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.

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