Molecular links between menarche and changes in the brain in women with migraine

偏头痛是一种复杂的、遗传性的、性二态性神经系统疾病，是一个主要的健康问题， 特别是对于育龄妇女。女性的发病率在治疗后急剧增加， 然而，这种增长的原因仍然难以捉摸。一种潜在的可能性是基因 在青春期出现的大脑中某些表型变化的倾向。事实上，发展 青春期大脑的变化可能会在疾病演变中产生个体性别特异性差异 弹道在偏头痛疾病中，许多研究指出存在性别特异性异常 在成年女性的大脑中。其中一些变化可能出现在青春期，因为 青春期大脑的变化是区域特异性的，有些区域在每个时期的变化更剧烈。 与其他人相比的成长阶段。我们的初步研究特别指出了两个潜在的地点， 在偏头痛的病理生理学、脑干和脑干中可能起主要作用的大脑易感性。这些 多项研究报告了结构、功能和功能连接性， 与偏头痛有关的异常我们的初步研究表明：i）女性专用塑料 成人偏头痛脑中相对于健康女性受试者的脑电变化不同于健康和 偏头痛男性受试者; ii）成人岛叶皮质灰质不变薄的异常模式 女性偏头痛患者; iii）在早期脑干发育率的性别相关差异 青春期发育阶段和iv）初潮年龄较早与偏头痛风险的关联（但不是 其他类型的头痛）在成年女性。由于卵巢类固醇激素分泌的启动和控制 通过控制青春期开始的“时间”的遗传机制，我们假设可能存在一种 青春期遗传机制与女性成年期偏头痛风险之间的联系。最近的一 全基因组关联研究（GWAS）的荟萃分析已经确定了100多个基因组位点， 初潮年龄是女性青春期的标志。在目标1中，我们建议确定以下的关联： 月经初潮遗传位点与偏头痛风险的大型女性队列研究（约48，000例患者，约150，000例对照）。的 确定重要的关联将为青春期与发育之间的分子联系提供令人信服的证据。 发展和女性偏头痛的风险。在目标2中，我们建议检查偏头痛与 通过分析大量的遗留临床MRI数据（1500 患者，900名对照）。在这些患者的一个子集（315例患者，420例对照）中，我们还建议探索 月经初潮遗传标记与偏头痛相关的大脑结构变化之间的关联。 确定偏头痛疾病和青春期发育之间的分子联系可能会更好地 了解疾病发生和进展的潜在机制，这将提供关键信息 用于发现新的药物靶点，以改变易感个体的偏头痛过程。

Migraine is a complex, hereditary, sexually-dimorphic neurological disorder that is a major health problem, particularly for reproductive-aged women. The incidence of the disease increases dramatically in females after puberty, however the cause of this increase still remains elusive. One potential possibility is a genetic predisposition to certain phenotypic changes in the brain that emerges during puberty. Indeed, developmental changes in the brain during the pubertal phase may create individual sex-specific variation in disease evolution trajectory. In migraine disease, a number of studies have pointed to the presence of sex-specific abnormalities in the adult female brain. It is likely that some of these changes may have appeared during puberty, since changes in the brain during puberty are region specific, with some regions changing more dramatically at each stage of growth compared to the others. Our preliminary studies particularly point to two potential sites of susceptibility in the brain that may play a major role in migraine pathophysiology, insula and brainstem. These regions are also implicated by multiple studies reporting structural, functional and functional connectivity abnormalities associated with migraine. Our preliminary studies have suggested: i) female-specific plastic changes in the insula in the adult migraine brain relative to healthy female subjects that differ from healthy and migraineur male subjects; ii) abnormal pattern of no thinning of the gray matter in the insular cortex of adult female migraineurs; iii) sex-related differences in the rate of the development of the brainstem during earlier stages of pubertal development and iv) association of earlier age at menarche with risk of migraine (but not other types of headaches) in adult women. Since ovarian steroid hormone secretion is initiated and governed by genetic mechanisms that control the `timing' of the initiation of puberty, we hypothesize that there may be a link between genetic mechanisms of puberty and risk of migraine in adulthood in women. A recent meta-analysis of genome-wide association studies (GWAS) has identified over 100 genomic loci that influence age at menarche, a marker of pubertal timing in females. In Aim 1, we propose to determine the association of menarche genetic loci with migraine risk in a large female cohort (~48,000 patients, ~150,000 controls). The identification of significant associations will provide compelling evidence for molecular links between pubertal development and migraine risk in females. In Aim 2, we propose to examine the relationship between migraine and structural brain changes in female patients by analyzing a large set of legacy clinical MRI data (1500 patients, 900 controls). In a subset of these patients (315 patients, 420 controls), we also propose to explore the association between menarche genetic markers and brain structural changes that are related to migraine. Identifying molecular links between migraine disease and pubertal development may allow for a better understanding of the mechanisms underlying disease onset and progression that will provide critical information for the discovery of novel drug targets for modifying the course of migraine in susceptible individuals.