Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Overview

Journal Ann Neurol

Specialty Neurology

Date 2021 Jun 28

PMID 34180076

Citations 12

Authors

Aster V E Harder

Bendik S Winsvold

Raymond Noordam

Lisanne S Vijfhuizen

Sigrid Borte

Lisette J A Kogelman

Irene de Boer

Erling Tronvik

Frits R Rosendaal

Ko Willems van Dijk

Emer OConnor

Carmen Fourier

Laurent F Thomas

Espen S Kristoffersen

Rolf Fronczek

Patricia Pozo-Rosich

Rigmor H Jensen

Michel D Ferrari

Thomas F Hansen

John-Anker Zwart

Gisela M Terwindt

Arn M J M van den Maagdenberg

Affiliations

Soon will be listed here.

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 (r < 0.1) with genomewide significance (p < 5 × 10 ), 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 = 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.

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