Abstract
BackgroundCluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Therefore, the circadian system has been suggested to play a crucial role in the pathophysiology of cluster headache. Cryptochromes are key components of the molecular clock generating circadian rhythms and have previously been shown to be associated with several psychiatric disorders, including seasonal affective disorder, bipolar disorder, and depression.MethodsIn this case-control study, we investigated the role of cryptochrome (CRY) genes in cluster headache by screening 628 cluster headache patients and 681 controls from Sweden for four known genetic variants in the CRY1 (rs2287161 and rs8192440) and CRY2 (rs10838524 and rs1554338) genes. In addition, we analyzed CRY1 gene expression in primary fibroblast cell lines from eleven patients and ten controls.ResultsThe exonic CRY1 variant rs8192440 was associated with cluster headache on allelic level (p=0.02) and this association was even more pronounced in a subgroup of patients with reported diurnal rhythmicity of attacks (p=0.002). We found a small significant difference in CRY1 gene expression between cluster headache patients and control individuals (p=0.04), but we could not identify an effect of the associated variant rs8192440 on CRY1 expression.ConclusionsWe discovered a disease-associated variant in the CRY1 gene and slightly increased CRY1 gene expression in tissue from cluster headache patients, strengthening the hypothesis of circadian dysregulation in cluster headache. How this gene variant may contribute to the pathophysiology of the disease remains subject to further studies.
Highlights
A striking feature of cluster headache (CH) is the circadian and circannual attack pattern by which the attacks repeatedly occur
The variant rs8192440 in the cryptochrome 1 (CRY1) gene is associated with CH in our Swedish case-control material where the major allele G was more common in patients than control individuals
A CRY1 haplotype including the rs8192440 major allele G was more common in cases compared to controls, but it was not stronger than the association of the rs8192440 polymorphism alone
Summary
A striking feature of cluster headache (CH) is the circadian and circannual attack pattern by which the attacks repeatedly occur. Diurnal rhythmicity of headache attacks occurs in 67–82% of all CH patients, it is hypothesized that the circadian system is dysregulated in CH [1,2,3]. Cluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Conclusions: We discovered a disease-associated variant in the CRY1 gene and slightly increased CRY1 gene expression in tissue from cluster headache patients, strengthening the hypothesis of circadian dysregulation in cluster headache. How this gene variant may contribute to the pathophysiology of the disease remains subject to further studies
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