Cluster Headache Genomewide Association Study and Meta‐Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
Authors: Winsvold Bendik S. , Harder Aster V. E. , Ran Caroline , Chalmer Mona A. , Dalmasso Maria Carolina , Ferkingstad Egil , Tripathi Kumar Parijat , Bacchelli Elena , Børte Sigrid , Fourier Carmen , Petersen Anja S. , Vijfhuizen Lisanne S. , Magnusson Sigurdur H. , O'Connor Emer , Bjornsdottir Gyda , Häppölä Paavo , Wang Yen‐Feng , Callesen Ida , Kelderman Tim , Gallardo Victor J , de Boer Irene , Olofsgård Felicia Jennysdotter , Heinze Katja , Lund Nunu , Thomas Laurent F. , Hsu Chia‐Lin , Pirinen Matti , Hautakangas Heidi , Ribasés Marta , Guerzoni Simona , Sivakumar Prasanth , Yip Janice , Heinze Axel , Küçükali Fahri , Ostrowski Sisse R. , Pedersen Ole B. , Kristoffersen Espen S. , Martinsen Amy E. , Artigas María S. , Lagrata Susie , Cainazzo Maria Michela , Adebimpe Joycee , Quinn Olivia , Göbel Carl , Cirkel Anna , Volk Alexander E. , Heilmann‐Heimbach Stefanie , Skogholt Anne Heidi , Gabrielsen Maiken E. , Wilbrink Leopoldine A. , Danno Daisuke , Mehta Dwij , Guðbjartsson Daníel F. ,   HUNT All‐In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium, Rosendaal Frits R. , Willems van Dijk Ko , Fronczek Rolf , Wagner Michael , Scherer Martin , Göbel Hartmut , Sleegers Kristel , Sveinsson Olafur A. , Pani Luca , Zoli Michele , Ramos‐Quiroga Josep A. , Dardiotis Efthimios , Steinberg Anna , Riedel‐Heller Steffi , Sjöstrand Christina , Thorgeirsson Thorgeir E. , Stefansson Hreinn , Southgate Laura , Trembath Richard C. , Vandrovcova Jana , Noordam Raymond , Paemeleire Koen , Stefansson Kari , Fann Cathy Shen‐Jang , Waldenlind Elisabet , Tronvik Erling , Jensen Rigmor H. , Chen Shih‐Pin , Houlden Henry , Terwindt Gisela M. , Kubisch Christian , Maestrini Elena , Vikelis Michail , Pozo‐Rosich Patricia , Belin Andrea C. , Matharu Manjit , van den Maagdenberg Arn M.J.M. , Hansen Thomas F. , Ramirez Alfredo , Zwart John‐Anker ,   for the International Consortium for Cluster Headache Genetics
Published: July 2023

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