Background

Cluster 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.

Methods

In 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.

Results

The 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.

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.

中文翻译：

---

分子钟基因隐花色素1（CRY1）及其在丛集性头痛中的作用

背景

丛集性头痛是一种严重的原发性头痛疾病，通常具有明显不同的昼夜节律发作模式。因此，昼夜节律系统被认为在丛集性头痛的病理生理学中起关键作用。隐花色素是产生昼夜节律的分子钟的关键组成部分，此前已证明与几种精神疾病有关，包括季节性情感障碍、双相情感障碍和抑郁症。

方法

在这项病例对照研究中，我们通过筛选来自瑞典的 628 名丛集性头痛患者和 681 名对照者的CRY1（rs2287161 和 rs8192440）和CRY2（rs10838524和 rs1554338）中的四种已知遗传变异，研究了隐花色素 ( CRY ) 基因在丛集性头痛中的作用) 基因。此外，我们分析了来自 11 名患者和 10 名对照的原代成纤维细胞系中CRY1基因的表达。

结果

外显子CRY1变体 rs8192440 与等位基因水平的丛集性头痛相关（p = 0.02），这种关联在报告有昼夜节律性发作的患者亚组中更为明显（p = 0.002）。我们发现丛集性头痛患者和对照个体之间的CRY1基因表达存在微小的显着差异（p = 0.04），但我们无法确定相关变体 rs8192440 对CRY1表达的影响。

结论

我们在丛集性头痛患者的组织中发现了CRY1基因中的疾病相关变异，并略微增加了CRY1基因的表达，从而加强了丛集性头痛中昼夜节律失调的假设。这种基因变异如何促成疾病的病理生理学仍有待进一步研究。