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

Elena Bacchelli; Maria Michela Cainazzo; Cinzia Cameli; Simona Guerzoni; Angela Martinelli; Michele Zoli; Elena Maestrini; Luigi Alberto Pini

doi:10.1186/s10194-016-0705-y

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

Elena Bacchelli, Maria Michela Cainazzo, Cinzia Cameli, Simona Guerzoni, Angela Martinelli, Michele Zoli, Elena Maestrini^*, Luigi Alberto Pini

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	114
Journal	Journal of Headache and Pain
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s10194-016-0705-y
Publication status	Published - 13 Dec 2016

Keywords

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

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Martinelli_2016_JHP_PACAPreceptor_CC
© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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Cite this

@article{9fa74ebb3a5e434f816fd73276b4b46d,

title = "A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants",

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)",

author = "Elena Bacchelli and Cainazzo, {Maria Michela} and Cinzia Cameli and Simona Guerzoni and Angela Martinelli and Michele Zoli and Elena Maestrini and Pini, {Luigi Alberto}",

note = "Supported by the Italian Ministry of Health (RF2009-1549619), University of Bologna (RFO).",

year = "2016",

month = dec,

day = "13",

doi = "10.1186/s10194-016-0705-y",

language = "English",

volume = "17",

journal = "Journal of Headache and Pain",

issn = "1129-2369",

publisher = "Springer-Verlag",

number = "1",

}

TY - JOUR

T1 - A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

AU - Bacchelli, Elena

AU - Cainazzo, Maria Michela

AU - Cameli, Cinzia

AU - Guerzoni, Simona

AU - Martinelli, Angela

AU - Zoli, Michele

AU - Maestrini, Elena

AU - Pini, Luigi Alberto

N1 - Supported by the Italian Ministry of Health (RF2009-1549619), University of Bologna (RFO).

PY - 2016/12/13

Y1 - 2016/12/13

N2 - 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.

AB - 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.

KW - Association studies in genetics

KW - Cluster headache

KW - Genome-Wide Association Study

KW - Membrane metalloendopeptidase (MME)

KW - Missense mutation

KW - Neprylisin

KW - Pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1)

U2 - 10.1186/s10194-016-0705-y

DO - 10.1186/s10194-016-0705-y

M3 - Article

AN - SCOPUS:85003890232

SN - 1129-2369

VL - 17

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

IS - 1

M1 - 114

ER -

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

Abstract

Keywords

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