Emer O'Connor1,2,3, Carmen Fourier4, Caroline Ran4, Jana Vandrovcova1, Henry Houlden1, Manjit Matharu3, Andrea Carmine Belin4, Prasanth Sivakumar1, Franziska Liesecke4, Laura Southgate5,6, Aster V E Harder7,8, 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 Grangeon3,19, Susie Lagrata3, Daisuke Danno3, Richard Trembath6, Nicholas W Wood1,2, Ingrid Kockum20, Bendik S Winsvold21,22,23, Anna Steinberg20, Christina Sjöstrand20, Elisabet Waldenlind20. 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.
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.
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.