Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.

中文翻译：

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利用遗传数据阐明偏头痛风险与大脑结构之间的关系。

偏头痛是一种非常常见且使人衰弱的疾病，经常影响个人在其生命中最富有成效的几年。先前的研究已经确定了与偏头痛风险相关的遗传变异和脑形态测量差异。然而，偏头痛和脑形态测量之间的关系尚未在遗传水平上进行检查，脑结构与偏头痛风险之间关联的因果性质尚未确定。使用迄今为止最大的可用全基因组关联研究，我们检查了偏头痛和颅内体积之间的全基因组遗传重叠，以及九个皮质下脑结构的区域体积。我们进一步将偏头痛和每个大脑结构之间遗传重叠的识别和生物学注释集中在偏头痛和大脑结构之间共享的基因组特定区域上。最后，我们使用孟德尔随机化方法检查了任何被检查的大脑区域的大小是否会导致偏头痛风险增加。我们观察到偏头痛风险与颅内容积之间存在显着的全基因组负遗传相关性（rG = -0.11，P = 1 × 10-3），但与任何皮层下区域无关。然而，我们确定了偏头痛和每个大脑结构之间共同相关的区域基因组重叠。这些共享基因组区域中的基因富集表明可能与神经元信号传导和血管调节有关。最后，我们提供了较小的总大脑之间可能存在因果关系的证据，海马和腹侧间脑体积与偏头痛风险增加，以及偏头痛风险增加与杏仁核体积增大之间的因果关系。我们利用大型全基因组关联研究的力量来展示共同影响偏头痛风险和几种大脑结构的共同遗传途径的证据，这表明高偏头痛风险个体的大脑形态测量改变可能是遗传介导的。对这些结果的进一步研究表明支持偏头痛病因的神经血管假说，并揭示了潜在的可行治疗靶点。我们利用大型全基因组关联研究的力量来展示共同影响偏头痛风险和几种大脑结构的共同遗传途径的证据，这表明高偏头痛风险个体的大脑形态测量改变可能是遗传介导的。对这些结果的进一步研究表明支持偏头痛病因的神经血管假说，并揭示了潜在的可行治疗靶点。我们利用大型全基因组关联研究的力量来展示共同影响偏头痛风险和几种大脑结构的共同遗传途径的证据，这表明高偏头痛风险个体的大脑形态测量改变可能是遗传介导的。对这些结果的进一步研究表明支持偏头痛病因的神经血管假说，并揭示了潜在的可行治疗靶点。