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

摘要 阿尔茨海默氏病（AD）在男性和女性中表现不同，但遗传和分子 推动这一趋势的因素在很大程度上仍然难以捉摸。AD是痴呆症最常见的原因，影响超过500万人 仅在美国，直到今天仍然基本上无法治疗。因为AD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，各种研究的证据表明， 是AD的重要组成部分。因此，以性别特异性的方式研究AD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，确定与性别相关的新的性别特异性风险因素 个性化的遗传医学，并发现潜在的新的AD药物靶点，可能有利于两性。 到目前为止，令人惊讶的是，很少有性别特异性变异/基因被鉴定出来，我们假设这是因为 先前的研究面临着一些障碍，如数据有限和未探索的研究途径。这 一个项目建议将大数据与最先进的方法结合使用，以利用既定的性别 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 全基因组关联研究（GWAS）通过使用更大的样本量和广泛协调的数据。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 协会.此外，我们将首次以性别特异性方式探索罕见变异对AD的作用。 目标2将使用与目标1平行的策略，但将重点放在X染色体上， 在AD遗传学领域尚未探索。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： 评估其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。同样地， 将使用AD相关内表型（例如， 脑脊液）。目标3将遵循一种不同的创新性方法- 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。然后将通过将后者与AD风险相关联来验证后者的变体。 该项目的独立阶段将侧重于使用多组学数据来证实性别特异性 基因与AD风险的关联，以及蛋白质组学数据，以发现新的AD风险基因。成功的核心 在这项提议中，Belloy博士将得到一个由遗传学、成像学和医学专家组成的专家组的支持。 神经学（Michael Greicius博士）、多组学数据整合（Stephen蒙哥马利博士）、蛋白质组学分析 (Dr. Nicholas Seyfried）、性二态（Marcia Stefanick博士）和罕见变异分析（Zihuai He博士）， 为他提供了必要的技能，以开始作为一个独立的科学家的职业生涯。

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.