Cluster Headache Genomewide Association Study and Meta‐Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
Bendik S. Winsvold, Aster V. E. Harder, Caroline Ran, Mona Ameri Chalmer, Carolina Dalmasso, Egil Ferkingstad, Kumar Parijat Tripathi, Elena Bacchelli, Sigrid Børte, Carmen Fourier, Anja Sofie Petersen, Lisanne S. Vijfhuizen, Sigurður H. Magnússon, Emer O’Connor, Gyða Björnsdóttir, Paavo Häppölä, Yen‐Feng Wang, Ida Callesen, Tim Kelderman, Victor J Gallardo, Irene de Boer, Felicia Jennysdotter Olofsgård, Katja Heinze, Nunu Lund, Laurent F. Thomas, Chia‐Lin Hsu, Matti Pirinen, Heidi Hautakangas, Marta Ribasés, Simona Guérzoni, Prasanth Sivakumar, Janice Yip, Axel Heinze, Fahri Küçükali, Sisse Rye Ostrowski, Ole Birger Pedersen, Espen Saxhaug Kristoffersen, Amy E. Martinsen, María Soler Artigas, Susie Lagrata, Maria Michela Cainazzo, Joycee Adebimpe, Olivia Quinn, Carl Göbel, Anna Cirkel, Alexander E. Volk, Stefanie Heilmann‐Heimbach, Anne Heidi Skogholt, Maiken E. Gabrielsen, Leopoldine A. Wilbrink, Daisuke Danno, Dwij Mehta, Daníel F. Guðbjartsson, Frits R. Rosendaal, Ko Willems van Dijk, Rolf Fronczek, Michael Wagner, Martin Scherer, Hartmut Göbel, Kristel Sleegers, Ólafur Sveinsson, Luca Pani, Michèle Zoli, Josep Antoni Ramos‐Quiroga, Efthimios Dardiotis, Anna Steinberg, Steffi G. Riedel‐Heller, Christina Sjöstrand, Thorgeir E. Thorgeirsson, Hreinn Stefánsson, Laura Southgate, Richard C. Trembath, Jana Vandrovcová, Raymond Noordam, Koen Paemeleire, Kari Stefansson, Cathy S.J. Fann, Elisabet Waldenlind, Erling Tronvik, Rigmor Jensen, Shih‐Pin Chen, Henry Houlden, Gisela M. Terwindt, Christian Kubisch, Elena Maestrini, Michail Vikelis, Patricia Pozo‐Rosich, Andrea Carmine Belin, Manjit Matharu, Arn M. J. M. van den Maagdenberg, Thomas Folkmann Hansen, Alfredo Ramı́rez, John‐Anker Zwart
Abstract
OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.