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

Bendik Winsvold; Aster V. E. A. Harder; Caroline Ran; Mona Chalmer; Maria Carolina Dalmasso; Egil Ferkingstad; Kumar Parijat Tripathi; Elena Bacchelli; Sigrid Borte; Carmen S. Fourier; Anja H. Petersen; Lisanne Vijfhuizen; Sigurdur Magnusson; Emer O'Connor; Gyda Bjornsdottir; Paavo Happola; Yen-Feng Wang; Ida Callesen; Tim Kelderman; Victor J. Gallardo; Irene de Boer; Felicia Jennysdotter Olofsgard; Katja Heinze; Nunu Lund; Laurent F. Thomas; Chia-Lin Hsu; Matti Pirinen; Heidi Hautakangas; Marta Ribases; Simona Guerzoni; Prasanth Sivakumar; Janice Yip; Axel Heinze; Fahri B. Kucukali; Sisse S. Ostrowski; Ole E. Pedersen; Espen S. Kristoffersen; Amy E. Martinsen; Maria S. Artigas; Susie Lagrata; Maria Michela Cainazzo; Joycee Adebimpe; Olivia Quinn; Carl E. Goebel; Anna Cirkel; Alexander Volk; Stefanie E. Heilmann-Heimbach; Anne Heidi Skogholt; Maiken E. Gabrielsen; Leopoldine A. Wilbrink; Daisuke Danno; Dwij R. Mehta; Daniel F. Guobjartsson; Frits R. Rosendaal; Ko Willems van Dijk; Rolf A. Fronczek; Michael Wagner; Martin Scherer; Hartmut A. Goebel; Kristel Sleegers; Olafur Sveinsson; Luca Pani; Michele Zoli; Josep A. Ramos-Quiroga; Efthimios Dardiotis; Anna Steinberg; Steffi Riedel-Heller; Christina Sjostrand; Thorgeir E. Thorgeirsson; Hreinn Stefansson; Laura Southgate; Richard C. Trembath; Jana Vandrovcova; Raymond Noordam; Koen H. Paemeleire; Kari Stefansson; Cathy Shen-Jang Fann; Elisabet Waldenlind; Erling Tronvik; Rigmor H. Jensen; Shih-Pin Chen; Henry Houlden; Gisela C. Terwindt; Christian Kubisch; Elena Maestrini; Michail Vikelis; Patricia Pozo-Rosich; Andrea C. Belin; Manjit Matharu; Arn M. J. M. van den Maagdenberg; Thomas F. Hansen; Alfredo Ramirez; John-Anker Zwart; Int Headache Genetics Consortium

doi:10.1002/ana.26743

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

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

Bendik Winsvold, Aster V. E. A. Harder, Caroline Ran, Mona Chalmer, Maria Carolina Dalmasso, Egil Ferkingstad, Kumar Parijat Tripathi, Elena Bacchelli, Sigrid Borte, Carmen S. Fourier, …

Annals of neurology, Vol.94(4), pp.713-726

2023-10-01

DOI: https://doi.org/10.1002/ana.26743

PMID: 37486023

Appears in Miller School of Medicine - Latest Publications

Abstract

Clinical Neurology

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Science & Technology

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.

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Title: Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
Creators: Bendik Winsvold - Oslo University Hospital
Aster V. E. A. Harder - Leiden University Medical Center
Caroline Ran - Karolinska Institutet
Mona Chalmer - Glostrup Hospital
Maria Carolina Dalmasso - University of Cologne
Egil Ferkingstad - deCODE Genetics
Kumar Parijat Tripathi - University Hospital Cologne
Elena Bacchelli - University of Bologna
Sigrid Borte - Oslo Univ Hosp, Dept Res & Innovat, Div Clin Neurosci, Oslo, Norway
Carmen S. Fourier - Karolinska Institutet
Anja H. Petersen - University of Copenhagen
Lisanne Vijfhuizen - Leiden University Medical Center
Sigurdur Magnusson - Amgen Inc, deCODE Genet, Reykjavik, Iceland
Emer O'Connor - UCL, Inst Neurol, Dept Neuromuscular Dis, London, England
Gyda Bjornsdottir
Paavo Happola - Institute for Molecular Medicine Finland
Yen-Feng Wang - Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan
Ida Callesen - Glostrup Hospital
Tim Kelderman - Ghent University Hospital
Victor J. Gallardo - Vall d'Hebron Institut de Recerca
Irene de Boer - Leiden University Medical Center
Felicia Jennysdotter Olofsgard - Karolinska Institutet
Katja Heinze - Clinical Research Center Kiel
Nunu Lund - Copenhagen University Hospital
Laurent F. Thomas - Norwegian University of Science and Technology
Chia-Lin Hsu - Acad Sinica, Inst Biomed Sci, Taipei, Taiwan
Matti Pirinen - University of Helsinki
Heidi Hautakangas - Institute for Molecular Medicine Finland
Marta Ribases - Vall d'Hebron Institut de Recerca
Simona Guerzoni - Azienda Ospedaliero-Universitaria di Modena
Prasanth Sivakumar - University College London
Janice Yip - University College London
Axel Heinze - Clinical Research Center Kiel
Fahri B. Kucukali - University of Antwerp
Sisse S. Ostrowski - Rigshospitalet
Ole E. Pedersen - Zealand Univ Hosp, Dept Clin Immunol, Koge, Denmark
Espen S. Kristoffersen - Oslo University Hospital
Amy E. Martinsen - Oslo University Hospital
Maria S. Artigas - Vall d'Hebron Institut de Recerca
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 E. Goebel - Kiel Migraine & Headache Ctr, Kiel, Germany
Anna Cirkel - University Hospital Schleswig-Holstein
Alexander Volk - University Medical Center Hamburg-Eppendorf
Stefanie E. Heilmann-Heimbach - University Hospital 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 R. Mehta - National Hospital for Neurology and Neurosurgery
Daniel F. Guobjartsson - Amgen Inc, deCODE Genet, Reykjavik, Iceland
Frits R. Rosendaal - Leiden University Medical Center
Ko Willems van Dijk - Leiden University Medical Center
Rolf A. Fronczek - Leiden University Medical Center
Michael Wagner - University Hospital Bonn
Martin Scherer - University Medical Center Hamburg-Eppendorf
Hartmut A. Goebel - Kiel Migraine & Headache Ctr, Kiel, Germany
Kristel Sleegers - University of Antwerp
Olafur Sveinsson - University of Iceland
Luca Pani - University of Miami
Michele Zoli - University of Modena and Reggio Emilia
Josep A. Ramos-Quiroga - Centro de Investigación Biomédica en Red de Salud Mental
Efthimios Dardiotis - University of Thessaly
Anna Steinberg - Karolinska Institutet
Steffi Riedel-Heller - Leipzig University
Christina Sjostrand - Karolinska Institutet
Thorgeir E. Thorgeirsson - deCODE Genetics
Hreinn Stefansson - deCODE Genetics
Laura Southgate - St George's, University of London
Richard C. Trembath - King's College London
Jana Vandrovcova - University College London
Raymond Noordam - Leiden University Medical Center
Koen H. Paemeleire - Ghent University Hospital
Kari Stefansson - Amgen
Cathy Shen-Jang Fann - Institute of Biomedical Sciences, Academia Sinica
Elisabet Waldenlind - Karolinska Institutet
Erling Tronvik - Norwegian University of Science and Technology
Rigmor H. Jensen - University of Copenhagen
Shih-Pin Chen - Natl Yang Ming Chiao Tung Univ, Brain Res Ctr, Taipei, Taiwan
Henry Houlden - University College London
Gisela C. Terwindt - Leiden University
Christian Kubisch - University Medical Center Hamburg-Eppendorf
Elena Maestrini - University of Bologna
Michail Vikelis - Base Training
Patricia Pozo-Rosich - Vall d'Hebron Institut de Recerca
Andrea C. Belin - Karolinska Institutet
Manjit Matharu - National Hospital for Neurology and Neurosurgery
Arn M. J. M. van den Maagdenberg - Leiden University Medical Center
Thomas F. Hansen - University of Copenhagen
Alfredo Ramirez - University of Cologne
John-Anker Zwart - Oslo Univ Hosp, Dept Res & Innovat, Div Clin Neurosci, Oslo, Norway
Int Headache Genetics Consortium
Publication Details: Annals of neurology, Vol.94(4), pp.713-726
Publisher: Wiley
Number of pages: 14
Grant note: 20200095; MOST-108-2314-B-010-022-MY3; 110-2326-B-A49A-501-MY3 / Karolinska Institutet Research Funds Research Funding Pool at Rigshospitalet 2017SGR1461 / Generalitat de Catalunya Swedish Brain Foundation Biomedical Network Research Center on Mental Health (CIBERSAM, Madrid, Spain) 01ED1619A / German Federal Ministry of Education and Research [BMBF]; Federal Ministry of Education & Research (BMBF) 6026337; W212163-2-64 / Netherlands Organization for Scientific Research; Netherlands Organization for Scientific Research (NWO) 2020034 / South-Eastern Norway Regional Health Authority PI18/01788; PI19/01224; PI20/00041 / Instituto de Salud Carlos III; Spanish Government Mellby Gard Foundation
Academic Unit: Miller School of Medicine; UMMG Dept of Psychiatry & Behavioral Sciences
Language: English
Resource Type: Journal article
PMID: 37486023
Record Identifier: 991032795823202976