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.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bacchelli
authors.affiliation: Headache and Drug Abuse Unit, Policlinico Hospital, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Maria Michela
authors.initials: MM
authors.lastname: Cainazzo
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cameli
authors.affiliation: Headache and Drug Abuse Unit, Policlinico Hospital, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Guerzoni
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy.|Present address: School of Medicine, University of St Andrews, St Andrews, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Martinelli
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy. elena.maestrini@unibo.it.
authors.forename: Elena
authors.identifier: http://orcid.org/0000-0001-5924-3179
authors.initials: E
authors.lastname: Maestrini
authors.affiliation: Center for Neuroscience and Neurotechnology, Policlinico Hospital, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100, Modena, Italy. luigialberto.pini@unimore.it.
authors.forename: Luigi Alberto
authors.initials: LA
authors.lastname: Pini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003027:Cluster Headache / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics*; D055815:Young Adult
chemical_list: D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D015260:Neprilysin
keywords: Association studies in genetics; Cluster headache; Genome-Wide Association Study; Membrane metalloendopeptidase (MME); Missense mutation; Neprylisin; Pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1)