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 A Chalmer; Maria Carolina Dalmasso; Egil Ferkingstad; Kumar Parijat Tripathi; Elena Bacchelli; Sigrid Børte; Carmen Fourier; Anja S Petersen; Lisanne S Vijfhuizen; Sigurdur H Magnusson; Emer O'Connor; Gyda Bjornsdottir; 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 Guerzoni; Prasanth Sivakumar; Janice Yip; Axel Heinze; Fahri Küçükali; Sisse R Ostrowski; Ole B Pedersen; Espen S Kristoffersen; Amy E Martinsen; María S 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; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium; Frits R Rosendaal; Ko Willems van Dijk; Rolf Fronczek; Michael Wagner; Martin Scherer; Hartmut Göbel; Kristel Sleegers; Olafur A Sveinsson; Luca Pani; Michele Zoli; Josep A Ramos-Quiroga; Efthimios Dardiotis; Anna Steinberg; Steffi Riedel-Heller; Christina Sjöstrand; Thorgeir E Thorgeirsson; Hreinn Stefansson; Laura Southgate; Richard C Trembath; Jana Vandrovcova; Raymond Noordam; Koen Paemeleire; Kari Stefansson; Cathy Shen-Jang Fann; Elisabet Waldenlind; Erling Tronvik; Rigmor H Jensen; Shih-Pin Chen; Henry Houlden; Gisela M 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; International Consortium for Cluster Headache Genetics

doi:10.1002/ana.26743

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

Ann Neurol. 2023 Oct;94(4):713-726. doi: 10.1002/ana.26743. Epub 2023 Aug 7.

Authors

Bendik S Winsvold^{1

2

3

4}, Aster V E Harder^{5

6}, Caroline Ran⁷, Mona A Chalmer⁸, Maria Carolina Dalmasso^{9

10}, Egil Ferkingstad¹¹, Kumar Parijat Tripathi¹², Elena Bacchelli¹³, Sigrid Børte^{1

2

4}, Carmen Fourier⁷, Anja S Petersen⁸, Lisanne S Vijfhuizen⁵, Sigurdur H Magnusson¹¹, Emer O'Connor¹⁴, Gyda Bjornsdottir¹¹, Paavo Häppölä¹⁵, Yen-Feng Wang^{16

17}, Ida Callesen⁸, Tim Kelderman¹⁸, Victor J Gallardo¹⁹, Irene de Boer⁶, Felicia Jennysdotter Olofsgård⁷, Katja Heinze²⁰, Nunu Lund⁸, Laurent F Thomas^{2

21

22

23}, Chia-Lin Hsu²⁴, Matti Pirinen^{15

25

26}, Heidi Hautakangas¹⁵, Marta Ribasés^{27

28

29

30}, Simona Guerzoni³¹, Prasanth Sivakumar¹⁴, Janice Yip¹⁴, Axel Heinze²⁰, Fahri Küçükali^{32

33}, Sisse R Ostrowski^{34

35}, Ole B Pedersen³⁶, Espen S Kristoffersen^{1

4

37

38}, Amy E Martinsen^{1

2

4

39}, María S Artigas^{27

28

29

30}, Susie Lagrata⁴⁰, Maria Michela Cainazzo³¹, Joycee Adebimpe¹⁴, Olivia Quinn¹⁴, Carl Göbel^{20

41}, Anna Cirkel^{20

41}, Alexander E Volk⁴², Stefanie Heilmann-Heimbach⁴³, Anne Heidi Skogholt², Maiken E Gabrielsen², Leopoldine A Wilbrink⁴⁴, Daisuke Danno⁴⁰, Dwij Mehta⁴⁰, Daníel F Guðbjartsson¹¹; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium; Frits R Rosendaal⁴⁵, Ko Willems van Dijk^{5

46

47}, Rolf Fronczek⁶, Michael Wagner^{48

49}, Martin Scherer⁵⁰, Hartmut Göbel²⁰, Kristel Sleegers^{32

33}, Olafur A Sveinsson⁵¹, Luca Pani^{52

53}, Michele Zoli⁵², Josep A Ramos-Quiroga^{27

28

29

54}, Efthimios Dardiotis⁵⁵, Anna Steinberg^{56

57}, Steffi Riedel-Heller⁵⁸, Christina Sjöstrand^{56

59}, Thorgeir E Thorgeirsson¹¹, Hreinn Stefansson¹¹, Laura Southgate^{60

61}, Richard C Trembath⁶¹, Jana Vandrovcova¹⁴, Raymond Noordam⁶², Koen Paemeleire¹⁸, Kari Stefansson^{11

51}, Cathy Shen-Jang Fann²⁴, Elisabet Waldenlind^{56

57}, Erling Tronvik^{4

63

64}, Rigmor H Jensen⁸, Shih-Pin Chen^{17

65}, Henry Houlden¹⁴, Gisela M Terwindt⁶, Christian Kubisch⁴², Elena Maestrini¹³, Michail Vikelis⁶⁶, Patricia Pozo-Rosich^{19

67}, Andrea C Belin⁷, Manjit Matharu⁴⁰, Arn M J M van den Maagdenberg^{5

6}, Thomas F Hansen^{8

68}, Alfredo Ramirez^{9

48

49

69

70}, John-Anker Zwart^{1

2

4

39}; International Consortium for Cluster Headache Genetics

Affiliations

¹ Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
² 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 (NTNU), Trondheim, Norway.
³ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁴ Norwegian Centre for Headache Research (NorHEAD), Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁵ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
⁷ Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, University of Copenhagen University Hospital, Glostrup, Denmark.
⁹ Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰ Neurosciences and Complex Systems Unit (EnyS), CONICET, Hospital El Cruce 'N. Kirchner', National University A. Jauretche (UNAJ), Florencio Varela, Argentina.
¹¹ deCODE genetics/Amgen Inc., Reykjavik, Iceland.
¹² Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry, Uniklinik Köln, Cologne, Germany.
¹³ Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
¹⁴ Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
¹⁵ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
¹⁶ Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁷ Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁸ Department of Neurology, Ghent University Hospital, Ghent, Belgium.
¹⁹ Headache and Neurological Pain Research Group, Vall d'Hebron Research Institute, Departament de Medicina, Universitat Autònoma de Barcelona, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
²⁰ Kiel Migraine and Headache Centre, Kiel, Germany.
²¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²² BioCore-Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²³ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
²⁵ Department of Public Health, University of Helsinki, Helsinki, Finland.
²⁶ Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
²⁷ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Universitat Autònoma de Barcelona, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
²⁸ Department of Psychiatry, Vall d'Hebron University Hospital, Barcelona, Spain.
²⁹ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
³⁰ Department of Genetics, Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
³¹ AOU Policlinico Modena, Modena University Hospital, Modena, Italy.
³² Complex Genetics of Alzheimer's Disease Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
³³ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
³⁴ Department of Clinical Immunology, Centre of Diagnostic Investigation, Rigshospitalet, Copenhagen, Denmark.
³⁵ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³⁶ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
³⁷ Department of General Practice, University of Oslo, Oslo, Norway.
³⁸ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
³⁹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴⁰ Headache and Facial Pain Group, University College London Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
⁴¹ Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany.
⁴² Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴³ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
⁴⁴ Department of Neurology, Zuyderland Hospital, Heerlen, The Netherlands.
⁴⁵ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁶ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁷ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁸ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
⁴⁹ German Center for Neurodegenerative Diseases (DZNE Bonn), Bonn, Germany.
⁵⁰ Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵¹ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁵² Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
⁵³ Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL.
⁵⁴ Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
⁵⁵ Department of Neurology, Faculty of Medicine, University of Thessaly, Volos, Greece.
⁵⁶ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵⁷ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
⁵⁸ Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
⁵⁹ Department of Neurology, Danderyd Hospital, Stockholm, Sweden.
⁶⁰ Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.
⁶¹ Department of Medical & Molecular Genetics, Faculty of Life Sciences & Medicine, King's College London, London, UK.
⁶² Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
⁶³ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁶⁴ Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁶⁵ Department of Medical Research, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶⁶ Glyfada Headache Center, Glyfada, Greece.
⁶⁷ Headache Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
⁶⁸ Novo Nordic Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
⁶⁹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX.
⁷⁰ Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany.

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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Cluster Headache* / epidemiology
Cluster Headache* / genetics
Female
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Humans
Male
Migraine Disorders*
Polymorphism, Single Nucleotide / genetics
Risk Factors
Smoking / adverse effects
Smoking / genetics

Abstract

Publication types

MeSH terms

Grants and funding