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J Headache Pain. 2016 Dec;17(1):114. Epub 2016 Dec 13.

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants.

Author information

1
Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy.
2
Headache and Drug Abuse Unit, Policlinico Hospital, University of Modena and Reggio Emilia, Modena, Italy.
3
Present address: School of Medicine, University of St Andrews, St Andrews, UK.
4
Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
5
Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy. elena.maestrini@unibo.it.
6
Center for Neuroscience and Neurotechnology, Policlinico Hospital, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100, Modena, Italy. luigialberto.pini@unimore.it.

Abstract

BACKGROUND:

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; 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.

METHODS:

We 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.

RESULTS:

Although 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.

CONCLUSIONS:

Our 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.

KEYWORDS:

Association studies in genetics; Cluster headache; Genome-Wide Association Study; Membrane metalloendopeptidase (MME); Missense mutation; Neprylisin; Pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1)

PMID:
27957625
PMCID:
PMC5153392
DOI:
10.1186/s10194-016-0705-y
[Indexed for MEDLINE]
Free PMC Article

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