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

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


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 languageEnglish
Article number114
JournalJournal of Headache and Pain
Issue number1
Publication statusPublished - 13 Dec 2016


  • 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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