Cluster Headache Genomewide Association Study and Meta‐Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor-Reference-Cited by-同舟云学术

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

Published:2023-08-07 Issue:4 Volume:94 Page:713-726
ISSN:0364-5134
Container-title:Annals of Neurology
language:en
Short-container-title:Annals of Neurology

Author:

Winsvold Bendik S.¹²³⁴^ORCID,Harder Aster V. E.⁵⁶^ORCID,Ran Caroline⁷,Chalmer Mona A.⁸,Dalmasso Maria Carolina⁹¹⁰,Ferkingstad Egil¹¹,Tripathi Kumar Parijat¹²,Bacchelli Elena¹³,Børte Sigrid¹²⁴,Fourier Carmen⁷^ORCID,Petersen Anja S.⁸,Vijfhuizen Lisanne S.⁵,Magnusson Sigurdur H.¹¹,O'Connor Emer¹⁴,Bjornsdottir Gyda¹¹,Häppölä Paavo¹⁵,Wang Yen‐Feng¹⁶¹⁷^ORCID,Callesen Ida⁸,Kelderman Tim¹⁸,Gallardo Victor J¹⁹,de Boer Irene⁶^ORCID,Olofsgård Felicia Jennysdotter⁷,Heinze Katja²⁰,Lund Nunu⁸,Thomas Laurent F.²²¹²²²³^ORCID,Hsu Chia‐Lin²⁴,Pirinen Matti¹⁵²⁵²⁶,Hautakangas Heidi¹⁵,Ribasés Marta²⁷²⁸²⁹³⁰,Guerzoni Simona³¹,Sivakumar Prasanth¹⁴,Yip Janice¹⁴,Heinze Axel²⁰,Küçükali Fahri³²³³,Ostrowski Sisse R.³⁴³⁵,Pedersen Ole B.³⁶,Kristoffersen Espen S.¹⁴³⁷³⁸^ORCID,Martinsen Amy E.¹²⁴³⁹,Artigas María S.²⁷²⁸²⁹³⁰,Lagrata Susie⁴⁰,Cainazzo Maria Michela³¹,Adebimpe Joycee¹⁴,Quinn Olivia¹⁴,Göbel Carl²⁰⁴¹,Cirkel Anna²⁰⁴¹,Volk Alexander E.⁴²,Heilmann‐Heimbach Stefanie⁴³,Skogholt Anne Heidi²,Gabrielsen Maiken E.²,Wilbrink Leopoldine A.⁴⁴,Danno Daisuke⁴⁰,Mehta Dwij⁴⁰,Guðbjartsson Daníel F.¹¹,Rosendaal Frits R.⁴⁵,Willems van Dijk Ko⁵⁴⁶⁴⁷,Fronczek Rolf⁶,Wagner Michael⁴⁸⁴⁹,Scherer Martin⁵⁰,Göbel Hartmut²⁰,Sleegers Kristel³²³³,Sveinsson Olafur A.⁵¹,Pani Luca⁵²⁵³,Zoli Michele⁵²,Ramos‐Quiroga Josep A.²⁷²⁸²⁹⁵⁴,Dardiotis Efthimios⁵⁵,Steinberg Anna⁵⁶⁵⁷,Riedel‐Heller Steffi⁵⁸,Sjöstrand Christina⁵⁶⁵⁹,Thorgeirsson Thorgeir E.¹¹,Stefansson Hreinn¹¹,Southgate Laura⁶⁰⁶¹^ORCID,Trembath Richard C.⁶¹,Vandrovcova Jana¹⁴,Noordam Raymond⁶²,Paemeleire Koen¹⁸,Stefansson Kari¹¹⁵¹,Fann Cathy Shen‐Jang²⁴,Waldenlind Elisabet⁵⁶⁵⁷,Tronvik Erling⁴⁶³⁶⁴,Jensen Rigmor H.⁸,Chen Shih‐Pin¹⁷⁶⁵^ORCID,Houlden Henry¹⁴,Terwindt Gisela M.⁶,Kubisch Christian⁴²,Maestrini Elena¹³,Vikelis Michail⁶⁶,Pozo‐Rosich Patricia¹⁹⁶⁷,Belin Andrea C.⁷^ORCID,Matharu Manjit⁴⁰,van den Maagdenberg Arn M.J.M.⁵⁶,Hansen Thomas F.⁸⁶⁸,Ramirez Alfredo⁹⁴⁸⁴⁹⁶⁹⁷⁰^ORCID,Zwart John‐Anker¹²⁴³⁹^ORCID, ,

Affiliation:

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

ObjectiveThe 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.MethodsA 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.ResultsThe 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.InterpretationThis 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

Funder

Central Norway Regional Health Authority

European Regional Development Fund

Instituto de Salud Carlos III

Ministero della Salute

Universiteit Leiden

Vetenskapsrådet

Wellcome Trust

Publisher

Wiley

Subject

Neurology (clinical),Neurology