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 Quinn; 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

doi:10.1002/ana.26150

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

Ann Neurol. 2021 Aug;90(2):193-202. doi: 10.1002/ana.26150. Epub 2021 Jul 14.

Authors

Emer O'Connor^#^{1

2

3}, Carmen Fourier^#⁴, Caroline Ran^#⁴, Prasanth Sivakumar¹, Franziska Liesecke⁴, Laura Southgate^{5

6}, Aster V E Harder^{7

8}, Lisanne S Vijfhuizen⁸, Janice Yip¹, Nicola Giffin⁹, Nicholas Silver¹⁰, Fayyaz Ahmed¹¹, Isabel C Hostettler¹, Brendan Davies¹², M Zameel Cader¹³, Benjamin S Simpson¹⁴, Roisin Sullivan¹, Stephanie Efthymiou¹, Joycee Adebimpe¹, Olivia Quinn¹, Ciaran Campbell¹⁵, Gianpiero L Cavalleri¹⁵, Michail Vikelis¹⁶, Tim Kelderman¹⁷, Koen Paemeleire¹⁷, Emer Kilbride¹⁸, Lou Grangeon^{3

19}, Susie Lagrata³, Daisuke Danno³, Richard Trembath⁶, Nicholas W Wood^{1

2}, Ingrid Kockum²⁰, Bendik S Winsvold^{21

22

23}, Anna Steinberg²⁰, Christina Sjöstrand²⁰, Elisabet Waldenlind²⁰, Jana Vandrovcova^#¹, Henry Houlden^#¹, Manjit Matharu^#³, Andrea Carmine Belin^#⁴

Affiliations

¹ Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
² Neurogenetics Laboratory, Institute of Neurology, University College London, London, UK.
³ Headache and Facial Pain Group, University College London Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
⁴ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Molecular and Clinical Sciences Research Institute, St George's, University of London, London, UK.
⁶ Department of Medical & Molecular Genetics, Faculty of Life Sciences & Medicine, King's College London, London, UK.
⁷ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁹ Neurology Department, Royal United Hospital, Bath, UK.
¹⁰ Walton Centre, Liverpool, UK.
¹¹ Department of Neurology, Hull Royal Infirmary, Hull, UK.
¹² Department of Neurology, University Hospital North Midlands National Health Service Trust, Stoke-on-Trent, UK.
¹³ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
¹⁴ Division of Surgery and Interventional Science, University College London, London, UK.
¹⁵ Science Foundation Ireland FutureNeuro Research Centre, Royal College of Surgeons, Ireland School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland Dublin, Dublin, Ireland.
¹⁶ Glyfada Headache Clinic, Glyfada, Greece.
¹⁷ Department of Neurology, Ghent University Hospital, Ghent, Belgium.
¹⁸ University College Hospital London, London, UK.
¹⁹ Department of Neurology, Rouen University Hospital, Rouen, France.
²⁰ Division of Neurology, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
²¹ Department of Research, Innovation, and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
²² K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
²³ Department of Neurology, Oslo University Hospital, Oslo, Norway.

^# Contributed equally.

PMID: 34184781
DOI: 10.1002/ana.26150

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.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Cluster Headache / diagnosis
Cluster Headache / epidemiology*
Cluster Headache / genetics*
Cohort Studies
Female
Genetic Loci / genetics*
Genetic Predisposition to Disease / epidemiology*
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods*
Humans
Male
Sweden / epidemiology
United Kingdom / epidemiology

Abstract

Publication types

MeSH terms

Grants and funding