Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

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Cluster Headache Genetics Working Group , Harder , A V E , Winsvold , B S , Noordam , R & Häppölä , P 2021 , ' Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache ' , Annals of Neurology , vol. 90 , no. 2 , pp. 203-216 .

Title: Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache
Author: Cluster Headache Genetics Working Group; Harder, Aster V.E.; Winsvold, Bendik S.; Noordam, Raymond; Häppölä, Paavo
Contributor organization: Complex Disease Genetics
Institute for Molecular Medicine Finland
Genomics of Neurological and Neuropsychiatric Disorders
University of Helsinki
Date: 2021-08
Language: eng
Number of pages: 14
Belongs to series: Annals of Neurology
ISSN: 0364-5134
Abstract: Objective: Identifying common genetic variants that confer genetic risk for cluster headache. Methods: We conducted a case–control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10−8), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33–1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37–1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26–1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54–0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203–216.
Description: Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Subject: 3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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