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Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache
Author(s) -
Harder Aster V.E.,
Winsvold Bendik S.,
Noordam Raymond,
Vijfhuizen Lisanne S.,
Børte Sigrid,
Kogelman Lisette J.A.,
Boer Irene,
Tronvik Erling,
Rosendaal Frits R.,
Willems van Dijk Ko,
O'Connor Emer,
Fourier Carmen,
Thomas Laurent F.,
Kristoffersen Espen S.,
Fronczek Rolf,
PozoRosich Patricia,
Jensen Rigmor H.,
Ferrari Michel D.,
Hansen Thomas F.,
Zwart JohnAnker,
Terwindt Gisela M.,
Maagdenberg Arn M.J.M
Publication year - 2021
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.26146
Subject(s) - linkage disequilibrium , genome wide association study , odds ratio , locus (genetics) , single nucleotide polymorphism , genetics , biology , genetic association , confidence interval , population , medicine , genotype , gene , environmental health
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 ( r 2 < 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 ( r 2 = 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