Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
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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
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Annals of Neurology |
| Vol/bind | 94 |
| Udgave nummer | 4 |
| Sider (fra-til) | 713-726 |
| ISSN | 0364-5134 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The authors want to thank both all participating patients and their general practitioners for their good collaboration. Additional acknowledgements are found in Table S33 . This work was funded by the South‐Eastern Norway Regional Health Authority (#2020034); the Swedish National Infrastructure for Computing (SNIC) at Uppmax, Uppsala University partially funded by the Swedish Research Council through grant agreement no. 2018‐05973; the Wellcome Trust under award 076113, 085475, and 090355; the Instituto de Salud Carlos III (PI18/01788, PI19/01224, and PI20/00041); the European Regional Development Fund (ERDF); the Biomedical Network Research Center on Mental Health (CIBERSAM, Madrid, Spain); the Agència de Gestió d'Ajuts Universitaris i de Recerca‐AGAUR, Generalitat de Catalunya (2017SGR1461); the Netherlands Organization for Scientific Research, ie, the Center of Medical System Biology established by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (to A.M.J.M.v.d.M.); the EU‐funded FP7 “EUROHEADPAIN” (grant no. 6026337 to A.M.J.M.v.d.M.); The NEO study, which comprised of the Dutch controls, was supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Centre, and by the Leiden University, Research Profile Area “Vascular and Regenerative Medicine”; A.V.E. Harder was sponsored by the Leiden University Fund/Fonds Mr. J.J. van Enter “Pro Universitate”, www.luf.nl (grant W212163‐2‐64). Part of the genotyping of the German sample was funded by the JPND EADB grant to AR (German Federal Ministry of Education and Research [BMBF] grant: 01ED1619A); the BMBF (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, and 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, and 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, and 01GY1322G); PainFACT (H2020‐2020‐848099) to T.E.T; Italian Ministry of Health (RF2009‐1549619); The Research Funding Pool at Rigshospitalet to M.A.C.; The Swedish Brain Foundation and the Mellby Gård Foundation (FO2020‐0006 and FO2022‐0001); Karolinska Institutet Research Funds (2018‐01738, 2020‐01411, and 2022‐01781); The Swedish Research Council (2017‐01096); the Region Stockholm (ALF project 20200095); the Ministry of Science and Technology, Taiwan [MOST‐108‐2314‐B‐010‐022‐MY3 and 110‐2326‐B‐A49A‐501‐MY3]. The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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