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Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.
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.
Affiliation
  • Winsvold BS; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
  • Harder AVE; 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.
  • Ran C; Department of Neurology, Oslo University Hospital, Oslo, Norway.
  • Chalmer MA; Norwegian Centre for Headache Research (NorHEAD), Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
  • Dalmasso MC; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • Ferkingstad E; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
  • Tripathi KP; Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • Bacchelli E; Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, University of Copenhagen University Hospital, Glostrup, Denmark.
  • Børte S; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Fourier C; Neurosciences and Complex Systems Unit (EnyS), CONICET, Hospital El Cruce 'N. Kirchner', National University A. Jauretche (UNAJ), Florencio Varela, Argentina.
  • Petersen AS; deCODE genetics/Amgen Inc., Reykjavik, Iceland.
  • Vijfhuizen LS; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry, Uniklinik Köln, Cologne, Germany.
  • Magnusson SH; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
  • O'Connor E; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
  • Bjornsdottir G; 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.
  • Häppölä P; Norwegian Centre for Headache Research (NorHEAD), Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
  • Wang YF; Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • Callesen I; Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, University of Copenhagen University Hospital, Glostrup, Denmark.
  • Kelderman T; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • Gallardo VJ; deCODE genetics/Amgen Inc., Reykjavik, Iceland.
  • de Boer I; Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
  • Olofsgård FJ; deCODE genetics/Amgen Inc., Reykjavik, Iceland.
  • Heinze K; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
  • Lund N; Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Thomas LF; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • Hsu CL; Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, University of Copenhagen University Hospital, Glostrup, Denmark.
  • Pirinen M; Department of Neurology, Ghent University Hospital, Ghent, Belgium.
  • Hautakangas H; 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.
  • Ribasés M; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
  • Guerzoni S; Centre for Cluster Headache, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • Sivakumar P; Kiel Migraine and Headache Centre, Kiel, Germany.
  • Yip J; Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, University of Copenhagen University Hospital, Glostrup, Denmark.
  • Heinze A; 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.
  • Küçükali F; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
  • Ostrowski SR; BioCore-Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
  • Pedersen OB; Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
  • Kristoffersen ES; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • Martinsen AE; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
  • Artigas MS; Department of Public Health, University of Helsinki, Helsinki, Finland.
  • Lagrata S; Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
  • Cainazzo MM; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
  • Adebimpe J; Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Universitat Autònoma de Barcelona, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
  • Quinn O; Department of Psychiatry, Vall d'Hebron University Hospital, Barcelona, Spain.
  • Göbel C; Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
  • Cirkel A; Department of Genetics, Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
  • Volk AE; AOU Policlinico Modena, Modena University Hospital, Modena, Italy.
  • Heilmann-Heimbach S; Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
  • Skogholt AH; Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
  • Gabrielsen ME; Kiel Migraine and Headache Centre, Kiel, Germany.
  • Wilbrink LA; Complex Genetics of Alzheimer's Disease Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
Ann Neurol ; 94(4): 713-726, 2023 10.
Article in En | MEDLINE | ID: mdl-37486023
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;94713-726.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cluster Headache / Migraine Disorders Type of study: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Female / Humans / Male Language: En Journal: Ann Neurol Year: 2023 Type: Article Affiliation country: Norway
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cluster Headache / Migraine Disorders Type of study: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Female / Humans / Male Language: En Journal: Ann Neurol Year: 2023 Type: Article Affiliation country: Norway