Cluster Headache Genomewide Association Study and Meta‐Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Bendik S. Winsvold(Oslo University Hospital), Aster V. E. Harder(Leiden University Medical Center), Caroline Ran(Karolinska Institutet), Mona Ameri Chalmer(University of Copenhagen), Carolina Dalmasso(Consejo Nacional de Investigaciones Científicas y Técnicas), Egil Ferkingstad(deCODE Genetics (Iceland)), Kumar Parijat Tripathi(University Hospital Cologne), Elena Bacchelli(University of Bologna), Sigrid Børte(Oslo University Hospital), Carmen Fourier(Karolinska Institutet), Anja Sofie Petersen(University of Copenhagen), Lisanne S. Vijfhuizen(Leiden University Medical Center), Sigurður H. Magnússon(deCODE Genetics (Iceland)), Emer O’Connor(University College London), Gyða Björnsdóttir(deCODE Genetics (Iceland)), Paavo Häppölä(University of Helsinki), Yen‐Feng Wang(National Yang Ming Chiao Tung University), Ida Callesen(University of Copenhagen), Tim Kelderman(Ghent University Hospital), Victor J Gallardo(Universitat Autònoma de Barcelona), Irene de Boer(Leiden University Medical Center), Felicia Jennysdotter Olofsgård(Karolinska Institutet), Katja Heinze(Clinical Research Center Kiel), Nunu Lund(University of Copenhagen), Laurent F. Thomas(Norwegian University of Science and Technology), Chia‐Lin Hsu(Institute of Biomedical Sciences, Academia Sinica), Matti Pirinen(Statistics Finland), Heidi Hautakangas(University of Helsinki), Marta Ribasés(Universitat Autònoma de Barcelona), Simona Guérzoni(Azienda Ospedaliero-Universitaria di Modena), Prasanth Sivakumar(University College London), Janice Yip(University College London), Axel Heinze(Clinical Research Center Kiel), Fahri Küçükali(University of Antwerp), Sisse Rye Ostrowski(University of Copenhagen), Ole Birger Pedersen(Zealand University Hospital Køge), Espen Saxhaug Kristoffersen(Oslo University Hospital), Amy E. Martinsen(Oslo University Hospital), María Soler Artigas(Universitat Autònoma de Barcelona), Susie Lagrata(National Hospital for Neurology and Neurosurgery), Maria Michela Cainazzo(Azienda Ospedaliero-Universitaria di Modena), Joycee Adebimpe(University College London), Olivia Quinn(University College London), Carl Göbel(University Hospital Schleswig-Holstein), Anna Cirkel(University Hospital Schleswig-Holstein), Alexander E. Volk(Universität Hamburg), Stefanie Heilmann‐Heimbach(University of Bonn), Anne Heidi Skogholt(Norwegian University of Science and Technology), Maiken E. Gabrielsen(Norwegian University of Science and Technology), Leopoldine A. Wilbrink(Zuyderland Medisch Centrum), Daisuke Danno(National Hospital for Neurology and Neurosurgery), Dwij Mehta(National Hospital for Neurology and Neurosurgery), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Frits R. Rosendaal(Leiden University Medical Center), Ko Willems van Dijk(Leiden University Medical Center), Rolf Fronczek(Leiden University Medical Center), Michael Wagner(University Hospital Bonn), Martin Scherer(Universität Hamburg), Hartmut Göbel(Clinical Research Center Kiel), Kristel Sleegers(University of Antwerp), Ólafur Sveinsson(University of Iceland), Luca Pani(University of Modena and Reggio Emilia), Michèle Zoli(University of Modena and Reggio Emilia), Josep Antoni Ramos‐Quiroga(Universitat Autònoma de Barcelona), Efthimios Dardiotis(University of Thessaly), Anna Steinberg(Karolinska University Hospital), Steffi G. Riedel‐Heller(Leipzig University), Christina Sjöstrand(Danderyds sjukhus), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Hreinn Stefánsson(deCODE Genetics (Iceland)), Laura Southgate(St George's, University of London), Richard C. Trembath(King's College London), Jana Vandrovcová(University College London), Raymond Noordam(Leiden University Medical Center), Koen Paemeleire(Ghent University Hospital), Kari Stefansson(deCODE Genetics (Iceland)), Cathy S.J. Fann(Institute of Biomedical Sciences, Academia Sinica), Elisabet Waldenlind(Karolinska University Hospital), Erling Tronvik(Norwegian University of Science and Technology), Rigmor Jensen(University of Copenhagen), Shih‐Pin Chen(National Yang Ming Chiao Tung University), Henry Houlden(University College London), Gisela M. Terwindt(Leiden University Medical Center), Christian Kubisch(Universität Hamburg), Elena Maestrini(University of Bologna), Michail Vikelis(Base Training), Patricia Pozo‐Rosich(Universitat Autònoma de Barcelona), Andrea Carmine Belin(Karolinska Institutet), Manjit Matharu(National Hospital for Neurology and Neurosurgery), Arn M. J. M. van den Maagdenberg(Leiden University Medical Center), Thomas Folkmann Hansen(University of Copenhagen), Alfredo Ramı́rez(The University of Texas at San Antonio Health Science Center), John‐Anker Zwart(Oslo University Hospital)
Annals of Neurology
July 24, 2023
10.1002/ana.26743
Cited by 61Open Access
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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.

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