Abstract
BackgroundCluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.MethodsWe have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH.ResultsAlthough no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 × 10−6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 × 10−5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin.ConclusionsOur study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.Electronic supplementary materialThe online version of this article (doi:10.1186/s10194-016-0705-y) contains supplementary material, which is available to authorized users.
Highlights
Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology
We conducted genome-wide association tests for single Single-nucleotide polymorphism (SNP), as well as gene-based tests focussing on a subset of rare protein altering variants (PAVs), which a priori, are more likely to impact on disease status
Genome wide association analysis Single marker case-control association analysis was performed on high quality SNPs with minor allele frequency (MAF) > 0.01 (290505 SNPs) in the study population, using the Fisher exact test (Additional file 1: Table S3)
Summary
Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; no confirmed gene associations have been identified. Cluster Headache (CH) is a primary headache with a mean prevalence of 0.1% among general population and a clear male predominance [1]. It is characterized by severe unilateral retro-orbital or fronto-temporal pain attacks, occurring even eight times a day and associated with homolateral autonomic signs [2]. Twin and family studies have indicated the importance of genetic factors in CH [1]. Genetic predisposition seems to be complex, with the environment and genetic factors interacting together [1]
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