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

偏头痛女性初潮与大脑变化之间的分子联系

• 批准号: 9226489
• 负责人: Nasim Maleki
• 金额: $ 25.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226489
• 关键词: Address; Adult; Affect; Age at Menarche; Brain; Brain Stem; Brain region; Cell Nucleus; Chemicals; Classic Migraine; Clinical; Clinical Data; Collaborations; Common Migraine; Complex; Data; Data Set; Development; Disease; Disease Progression; Event; Evolution; Female; Functional disorder; Future; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Growth; Headache; Health; Hemorrhage; Hormonal Change; Incidence; Individual; Inherited; Insula of Reil; International; Life; Link; Magnetic Resonance Imaging; Measurable; Measures; Menarche; Meta-Analysis; Methods; Migraine; Molecular; Onset of illness; Ovarian Steroid Hormone; Pain; Patients; Pattern; Phase; Play; Predisposition; Process; Prospective Studies; Puberty; Regulation; Reporting; Reproductive Behavior; Risk; Role; Sex Characteristics; Signal Pathway; Site; Staging; Structure; Thick; Time; Variant; Woman; aged; biobank; brain abnormalities; clinical care; cohort; experience; genome wide association study; girls; gray matter; hormone regulation; improved; male; men; nervous system disorder; neuroimaging; new therapeutic target; patient subsets; pubertal timing; repository; reproductive; sex

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.

偏头痛是一种复杂的，遗传性的，性杀伤性神经系统疾病，是一个主要的健康问题， 特别是对于生殖时代的妇女。在女性中，疾病的发生率急剧增加 青春期，但是这种增加的原因仍然难以捉摸。一种潜在的可能性是遗传 青春期中出现的某些表型变化的易感性。确实，发展性 青春期期间大脑的变化可能会导致疾病进化的个别性别特异性变化 弹道。在偏头痛中，许多研究表明存在性别特异性异常 在成年女性大脑中。这些变化中的一些可能在青春期出现，因为 青春期期间大脑的变化是特定于区域的，某些区域在每个区域都更加急剧变化 与其他人相比，增长阶段。我们的初步研究尤其指出了两个潜在地点 大脑中可能在偏头痛病理生理学，岛状和脑干中起主要作用的敏感性。这些 区域还与多项研究有关结构，功能和功能连通性的研究牵涉 与偏头痛有关的异常。我们的初步研究建议：i）特定于女性的塑料 与健康的女性受试者相对于健康和健康的女性受试者，岛脱头大脑中的绝缘体变化，这与健康和 偏头痛男性受试者； ii）成人岛状皮质中没有灰质变薄的异常模式 女性偏头痛； iii）早期脑干发展速率的性别相关差异 青春期开发和IV的阶段）初级成年年龄与偏头痛的风险（但没有） 成年女性的其他类型的头痛）。由于卵巢类固醇激素分泌被启动并管理 通过控制青春期开始的“时机”的遗传机制，我们假设可能有一个 在女性成年期，青春期的遗传机制与偏头痛风险之间的联系。最近 全基因组关联研究（GWAS）的荟萃分析已鉴定出100多个基因组基因座影响 初潮的年龄，是女性青春期时机的标志。在AIM 1中，我们建议确定 一级遗传基因座的偏头痛风险在一个大型女性队列中（约48,000名患者，约150,000例对照）。这 识别重要的关联将为青春期之间的分子联系提供令人信服的证据 女性的发展和偏头痛风险。在AIM 2中，我们建议检查偏头痛之间的关系 通过分析大量遗产临床MRI数据，女性患者的结构性大脑变化（1500 患者，900个对照）。在这些患者的一部分（315例患者，420例对照）中，我们还建议探索 初级遗传标记和与偏头痛有关的大脑结构变化之间的关联。 识别偏头痛疾病与青春期发育之间的分子联系可能会更好 了解将提供关键信息的疾病发作和进展的机制 为了发现新的药物靶标，以修改易感人群偏头痛的过程。