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Background  Cluster headache (CH), a rare primary headache disorder, is currently thought to be a genetic susceptibility which play a role in CH susceptibility. A large numbers of genetic association studies have confirmed that the  HCRTR2  (Hypocretin Receptor 2) SNP rs2653349, and the  ADH4  (Alcohol Dehydrogenase 4) SNP rs1126671 and rs1800759 polymorphisms are linked to CH. In addition, the  CLOCK  (Circadian Locomotor Output Cycles Kaput) gene is becoming a research hotspot for CH due to encoding a transcription factor that serves as a basic driving force for circadian rhythm in humans. The purpose of this study was to evaluate the association between CH and the  HCRTR2, ADH4  and  CLOCK  genes in a Chinese CH case–control sample.    Methods  We genotyped polymorphisms of nine single nucleotide polymorphisms (SNPs) in the  HCRTR2, ADH4  and  CLOCK  genes to perform an association study on a Chinese Han CH case-control sample (112 patients and 192 controls),using Sequenom MALDI-TOF mass spectrometry iPLEX platform. The frequencies and distributions of genotypes and haplotypes were statistically compared between the case and control groups to identify associations with CH. The effects of SNPs on CH were further investigated by multiple logistic regression.    Results  The frequency of the  HCRTR2  SNP rs3800539 GA genotype was significantly higher in cases than in controls (48.2% vs.37.0%). The GA genotypes was associated with a higher CH risk (OR = 1.483, 95% CI: 0.564-3.387,  p  = 0.038), however, after Bonferroni correction, the association lost statistical significance. Haplotype analysis of the  HCRTR2  SNPs showed that among eight haplotypes, only H1-GTGGGG was linked to a reduced CH risk (44.7% vs. 53.1%, OR = 0.689, 95% CI =0.491~0.966,  p  = 0.030). No significant association of  ADH4 ,  CLOCK  SNPs with CH was statistically detected in the present study.    Conclusions  Association between  HCRTR2, ADH4,CLOCK  gene polymorphisms and CH was not significant in the present study, however, haplotype analysis indicated H1-GTGGGG was linked to a reduced CH risk.    Electronic supplementary material  The online version of this article (10.1186/s10194-017-0831-1) contains supplementary material, which is available to authorized users.

Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study