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- Title
Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache.
- Authors
Harder, Aster V.E.; Winsvold, Bendik S.; Noordam, Raymond; Vijfhuizen, Lisanne S.; Børte, Sigrid; Kogelman, Lisette J.A.; de Boer, Irene; Tronvik, Erling; Rosendaal, Frits R.; Willems van Dijk, Ko; O'Connor, Emer; Fourier, Carmen; Thomas, Laurent F.; Kristoffersen, Espen S.; Fronczek, Rolf; Pozo‐Rosich, Patricia; Jensen, Rigmor H.; Ferrari, Michel D.; Hansen, Thomas F.; Zwart, John‐Anker
- Abstract
<bold>Objective: </bold>Identifying common genetic variants that confer genetic risk for cluster headache.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Interpretation: </bold>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.
- Subjects
TRONDHEIM (Norway); CLUSTER headache; GENETIC variation; GENETIC disorders; LINKAGE disequilibrium; RNA sequencing
- Publication
Annals of Neurology, 2021, Vol 90, Issue 2, p203
- ISSN
0364-5134
- Publication type
journal article
- DOI
10.1002/ana.26146