Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40–70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer’s disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.

中文翻译：

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功能基因网络揭示了偏头痛家族中不同的分离机制。

偏头痛是全世界最常见的神经系统疾病，已证明它具有复杂的多基因起源，遗传力估计为 40-70%。常见和罕见的遗传变异被认为是常见类型偏头痛、典型先兆偏头痛和无先兆偏头痛的病理生理学基础。然而，到目前为止，仅发现了常见的变体。在这里，我们通过系统遗传学方法，整合来自可能与偏头痛病理有关的大脑和血管组织的RNA测序数据，并结合117个偏头痛家族的全基因组测序，首次识别出具有罕见突变的基因模块。基于单核 RNA 测序数据，我们在视觉皮层中发现了一个基因模块，该模块增加了偏头痛家族中的罕见突变，并在由 1930 名患者组成的第二个独立队列中复制了这一情况。该模块主要由中间神经元、锥体CA1和锥体SS细胞表达，通路分析显示与激素信号通路（促甲状腺素释放激素受体和催产素受体信号通路）、阿尔茨海默病通路、血清素受体通路和一般异三聚体G蛋白相关信号通路。我们的结果表明，罕见的功能基因变异与偏头痛的病理生理学密切相关。此外，我们预计这些结果可用于解释偏头痛背后的关键机制，并有可能改善偏头痛患者的治疗方案。