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

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.

Emerging relevance of circadian rhythms in headaches and neuropathic pain

“…20 Preliminary studies also suggest cluster headache-associated changes in other molecules indirectly modulated by the SCN, including PACAP, orexin, orexin receptors, testosterone, prolactin and growth hormone. [76][77][78][79][80][81][82] Although earlier attempts did not identify a molecular association of clock genes with cluster headache, [83][84][85] more recent studies elucidated changes in circadian transcriptiontranslation feedback loops. In an association study of large Swedish cohorts, a single-nucleotide polymorphism (SNP: rs12649507) in the Clock gene was found to be significantly associated with cluster headache.…”

Linking Cigarette Smoking/Tobacco Exposure and Cluster Headache: A Pathogenesis Theory

“…51,52 Another candidate gene set is NR3C2 and NR3C1. 56 This genetic variant encodes for a zincdependent plasma membrane endopeptidase known as neprilysin, which hydrolyzes several extracellular peptides, including neuropeptide Y, substance P, bradykinin, and enkephalins, which are involved in the central regulation of pain, sleep, and trigeminal nociception. These receptors are abundant in the hypothalamic-pituitary-adrenal (HPA) axis.…”

“…53,54 These are glucocorticoid receptors genes, which have been linked to smoking susceptibility, especially NC3R2. 56 The research group speculated that this genetic variant may increase susceptibility for CH by interacting with other environmental or genetic factors. The NR3C1 gene has also been linked to susceptibility to the development of depression and bipolar disorder.…”

“…54 Finally, an Italian group recently noted a MME c.674G > C (p.G225A) missense variant as a possible susceptibility gene for cluster headache. 56 This genetic variant encodes for a zincdependent plasma membrane endopeptidase known as neprilysin, which hydrolyzes several extracellular peptides, including neuropeptide Y, substance P, bradykinin, and enkephalins, which are involved in the central regulation of pain, sleep, and trigeminal nociception. 56 The research group speculated that this genetic variant may increase susceptibility for CH by interacting with other environmental or genetic factors.…”

“…56 This genetic variant encodes for a zincdependent plasma membrane endopeptidase known as neprilysin, which hydrolyzes several extracellular peptides, including neuropeptide Y, substance P, bradykinin, and enkephalins, which are involved in the central regulation of pain, sleep, and trigeminal nociception. 56 The research group speculated that this genetic variant may increase susceptibility for CH by interacting with other environmental or genetic factors. As cadmium displaces zinc in many metallo-enzymes and many of the symptoms of cadmium toxicity can be traced to a cadmium-induced zinc deficiency, this susceptibility gene could be activated by cadmium intoxication and fit into a cadmium-epigenetic model of CH pathogenesis.…”