Elucidating sex-specific risk for Alzheimer's disease through state-of-the-art genetics and multi-omics

摘要 阿尔茨海默病(AD)在男性和女性中表现不同，但基因和分子水平 推动这一趋势的因素在很大程度上仍然难以捉摸。AD是导致痴呆症的最常见原因，影响了500多万人 仅在美国，直到今天，基本上仍然是无法治愈的。因为阿尔茨海默病有很强的遗传性 遗传估计在50%-80%之间，研究AD的遗传学可以重要地帮助 发现新的药物靶点。然而，来自各种研究的证据表明，性别差异 是AD不可分割的一部分。因此，以性别特有的方式研究阿尔茨海默病的遗传学至关重要，因为这将 帮助该领域获得对疾病病理生理学的重要见解，识别与性别相关的新的风险因素 个性化基因药物，并发现潜在的AD药物靶点，可能对两性都有利。 到目前为止，令人惊讶的是几乎没有性别特异性变异/基因被识别出来，我们假设这是因为 之前的研究面临着几个障碍，如数据限制和未探索的研究途径。这 该项目建议将大数据与最先进的方法结合使用，以利用已建立的性别 AD的差异作为阐明新的AD风险基因的手段。目标1将改进先前的性别分层 通过使用更大的样本量和广泛协调的数据，进行全基因组关联研究。这 包括跨队列表型协调和使用年龄信息改善AD风险的强大模型 联想。此外，我们将首次探索罕见的变异在AD中的作用，以性别特有的方式。 目标2将使用与目标1类似的策略，但将重点放在X染色体上，该染色体在很大程度上仍保留着 在阿尔茨海默病遗传学领域没有被探索过。对于目标1和目标2，我们将通过以下方式进一步验证假定的关联 评估它们对脑组织中基因转录表达和蛋白质水平的性别特异性影响。同样， 将使用AD相关的内表型(例如，在 脑脊液)来自表型较深的队列。目标3将遵循一种不同的创新性爱方法- 通过鉴定脑组织中性别特异性AD相关蛋白的变化并确定 驱动它们的基因变异。后一种变种将通过将它们与AD的风险联系起来进行验证。 该项目的独立阶段将侧重于使用多组学数据来证实特定性别 与AD风险相关的基因，以及发现新的AD风险基因的蛋白质组学数据。成功的关键 对于这项提议，贝洛伊博士将得到一个在遗传学、成像学和 神经学(Michael Greicius博士)、多组学数据集成(Stephen Montgomery博士)、蛋白质组学分析 (尼古拉斯·塞弗里德博士)，性二型(马西娅·斯蒂芬尼克博士)，以及罕见的变异分析(何子怀博士)， 为他提供了作为一名独立科学家开始职业生涯所需的技能。

ABSTRACT Alzheimer’s disease (AD) manifests itself differently across men and women, but the genetic and molecular factors that drive this remain largely elusive. AD is the most common cause of dementia, affecting over 5 million people in the USA alone, and till today remains essentially untreatable. Because AD has a strong genetic component, with inheritance estimates between 50-80%, studying the genetics of AD can importantly aid the discovery of novel drug targets. However, evidence from various lines of research suggests that sex differences are an integral part of AD. It is therefore crucial to study the genetics of AD in a sex-specific manner, as this will help the field gain important insights into disease pathophysiology, identify novel sex-specific risk factors relevant to personalized genetic medicine, and uncover potential new AD drug targets that may benefit both sexes. To date, surprisingly few sex-specific variants/genes have been identified, which we hypothesize is because prior studies were faced with several obstacles such as data limitations and unexplored research avenues. This project proposes to use big data together with state-of-the-art approaches in order to leverage established sex differences in AD as a means of elucidating novel AD risk genes. Aim 1 will improve on prior sex-stratified genome-wide association studies (GWAS) by using larger sample sizes and extensively harmonized data. This includes a cross-cohort phenotype harmonization and powerful models using age information to improve AD risk associations. In addition, we will, for the first time, explore the role of rare variants on AD in a sex-specific manner. Aim 2 will use parallel strategies to Aim 1, but will focus on the X chromosome, which has remained largely unexplored in the field of AD genetics. For both Aims 1 and 2, we will further validate putative associations by evaluating their sex-specific effects on gene transcript expression and protein levels in brain tissue. Similarly, associations will be validated in a sex-specific manner using AD-relevant endophenotypes (e.g. tau levels in the cerebrospinal fluid) from deeply phenotyped cohorts. Aim 3 will follow a different innovative approach to sex- specific AD gene discovery by identifying sex-specific AD-related protein changes in brain tissue and determining the genetic variants that drive them. The latter variants will then be validated by relating them to risk for AD. The independent phase of this project will focus on the use of multi-omics data to corroborate sex-specific gene associations with AD risk, as well as proteomics data to discover new AD risk genes. Central to the success of this proposal, Dr. Belloy will have the support from an established group of experts in genetics, imaging, and neurology (Dr. Michael Greicius), multi-omics data integration (Dr. Stephen Montgomery), proteomics analyses (Dr. Nicholas Seyfried), sexual dimorphism (Dr. Marcia Stefanick), and rare variant analyses (Dr. Zihuai He), providing him with the necessary skillsets to embark on a career as an independent scientist.