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

ABSTRACT: 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.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.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.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.

SUBMITTER: Bacchelli E

PROVIDER: S-EPMC5153392 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Bacchelli Elena E Cainazzo Maria Michela MM Cameli Cinzia C Guerzoni Simona S Martinelli Angela A Zoli Michele M Maestrini Elena E Pini Luigi Alberto LA

The journal of headache and pain 20161213 1

<h4>Background</h4>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.<h4>Methods</h4>We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients ...[more]

PMID: 27957625

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Project description:ObjectiveThe purpose of this study was to investigate the HCRTR2 gene variants rs3122156, rs2653342, and rs2653349 in a large homogenous Swedish case-control cohort in order to further evaluate the possible contribution of HCRTR2 to cluster headache.BackgroundCluster headache is a severe neurovascular disorder and the pathophysiology is not yet fully understood. Due to striking circadian and circannual patterns of this disease, the hypothalamus has been a research focus in cluster headache. Several studies with many different cohorts from Europe have investigated the hypocretin receptor 2 (HCRTR2) gene, which is expressed in the hypothalamus. In particular, one HCRTR2 single nucleotide polymorphism, rs2653349, has been subject to a number of genetic association studies on cluster headache, with conflicting results. Two other HCRTR2 gene variants, rs2653342 and rs2653349, have been reported to be linked to cluster headache in an Italian study.MethodsWe genotyped a total of 517 patients diagnosed with cluster headache and 581 controls, representing a general Swedish population, for rs3122156, rs2653342, and rs2653349 using quantitative real-time PCR. Statistical analyses of genotype, allele, and haplotype frequencies for the 3 gene variants were performed comparing patients and controls.ResultsFor rs3122156, the minor allele frequency in patients was 25.9% compared to 29.9% in controls (P = .0421). However, this significance did not hold after correction for multiple testing. The minor allele frequencies for rs2653342 (14.7% vs 14.7%) and rs2653349 (19.5% vs 18.8%) were similar for patients and controls. Furthermore, we found one haplotype that was significantly less common in patients than controls (P = .0264). This haplotype included the minor allele for rs3122156 and the major alleles for rs2653342 and rs2653349. Significance did not hold after applying a permutation test.ConclusionsOur data show a trend for association between cluster headache and the HCRTR2 polymorphism rs3122156, where the minor allele seems to be a protective factor. However, the other 2 HCRTR2 gene variants, including the previously reported rs2653349, were not associated with cluster headache in our Swedish material. A comparison with previous studies points to variance in genotype and allele frequencies among the different populations, which most likely contributes to the opposing results regarding rs2653349. Although the results from this study do not strongly support an association, HCRTR2 remains an interesting candidate gene for involvement in the pathophysiology of cluster headache.

Project description:BackgroundCluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan.MethodsWe conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed.ResultsWe enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10-16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10-13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10-8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache.ConclusionsThis study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

Project description:BackgroundThe glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements.FindingsSignificantly decreased L-kynurenine (KYN, p < 0.01), while increased quinolinic acid (QUINA, p < 0.005) plasma concentrations were detected in the interbout period of CH patients compared to healthy subjects. The levels of KYN are further reduced during the ictal period compared to the controls (p < 0.006). There was a moderate, negative correlation between disease duration and interbout QUINA levels (p < 0.048, R = - 0.459); and between the total number of CH attacks experienced during the lifetime of patients and the interbout KYN concentrations (p < 0.024, R = - 0.516). Linear regression models revealed negative associations between age and levels of Trp, kynurenic acid, 3-hdyroxyanthranilic acid and QUINA in healthy control subjects, as well as between age and ictal level of anthranilic acid.ConclusionsOur results refer to a specifically altered Trp metabolism in CH patients. The onset of metabolic imbalance can be attributed to the interbout period, where the decreased KYN level is unable to perform its protective functions, while the concentration of QUINA, as a toxic compound, increases. These processes can trigger CH attacks, which may be associated with glutamate excess induced neurotoxicity, neuroinflammation and oxidative stress. Further studies are needed to elucidate the exact functions of these molecular alterations that can contribute to identify new, potential biomarkers in the therapy of CH.

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

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

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