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

通过最先进的遗传学和多组学阐明阿尔茨海默病的性别特异性风险

• 批准号: 10676963
• 负责人: Michael Belloy
• 金额: $ 13.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676963
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Amyloid; Big Data; Biology; Brain; Cerebrospinal Fluid; Clinical; Cognitive; Coupled; Data; Data Set; Dementia; Disease; Disease Progression; Drug Targeting; Energy Metabolism; Fellowship; Functional disorder; Genes; Genetic; Genetic Diseases; Genetic Medicine; Genetic Risk; Genetic Transcription; Genetic study; Genome; Goals; Image; Late Onset Alzheimer Disease; Learning; Link; Maps; Mentors; Methods; Modeling; Molecular; Molecular Disease; Multiomic Data; Mus; Neurology; Outcome; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Persons; Phase; Phenotype; Postdoctoral Fellow; Proteins; Proteomics; Research; Resources; Risk Factors; Role; Sample Size; Sampling; Scientist; Series; Sex Bias; Sex Differences; Source; Statistical Models; Thick; Time; Training; Transcript; United States; Validation; Variant; Woman; Work; X Chromosome; apolipoprotein E-4; autosome; brain tissue; candidate validation; career; cohort; data harmonization; data integration; differential expression; endophenotype; exome; gene discovery; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; genotypic sex; hazard; high risk; improved; innovation; insight; large datasets; men; multiple omics; new therapeutic target; novel; precision genetics; programs; proteomic signature; rare variant; risk variant; sex; sexual dimorphism; skills; success; tau Proteins

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.

抽象的 阿尔茨海默氏病（AD）在男性和女性中表现出不同的表现，但遗传和分子 推动这一驱动的因素仍然难以捉摸。广告是痴呆症的最常见原因，影响超过500万 仅美国的人们，直到今天，基本上仍然无法治疗。因为AD具有很强的遗传 遗传估计值在50-80％之间，研究AD的遗传学可以有助于帮助 发现新型药物靶标。但是，来自各种研究的证据表明性别差异 是AD的组成部分。因此，以性别特定方式研究AD的遗传学至关重要，因为这将会 帮助该领域获得对疾病病理生理学的重要见解，确定新颖的性别特异性风险因素相关 为个性化的遗传医学，并发现可能受益于男女的潜在新AD药物靶标。 迄今 先前的研究面临着几个障碍，例如数据限制和意外的研究途径。这 项目建议使用大数据以及最先进的方法，以利用已建立的性爱 AD的差异是阐明新型AD风险基因的一种手段。 AIM 1将改善先前的性别分层 全基因组关联研究（GWAS）通过使用较大的样本量和广泛统一的数据。这 包括跨核心表型协调和使用年龄信息来改善广告风险的强大模型 协会。此外，我们将首次以性别特定方式探索稀有变体对AD的作用。 AIM 2将使用平行的策略来实现目标1，但将专注于X染色体，该染色体在很大程度上仍然存在 在AD遗传学领域未开发。对于两个目标1和2，我们将通过 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。相似地， 关联将使用与广告相关的内表型以性别特定的方式进行验证（例如，tau水平 来自深层表型队列的脑脊液。 AIM 3将遵循不同的创新方法 - 通过鉴定性别特异性广告相关的蛋白质变化并确定，发现特定的AD基因发现 驱动它们的遗传变异。然后，将后一种变体通过将它们与AD风险联系起来来验证。 该项目的独立阶段将集中于使用多摩斯数据来证实性别特定的性别 具有AD风险的基因关联以及蛋白质组学数据，以发现新的AD风险基因。成功的中心 在这项建议中，贝尔洛伊博士将得到一群遗传学，成像和成像专家的支持 Neurology（Michael Greicius博士），多摩斯数据集成（Stephen Montgomery博士），蛋白质组学分析 （Nicholas Seyfried博士），性二态性（Marcia Stefanick博士）和罕见的变体分析（Zihuai博士）， 为他提供必要的技能，从而从事独立科学家的职业。

项目成果

APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.

APOE - Δ 4 和 BIN1 会增加阿尔茨海默病病理学的风险，但不会增加路易体病理学的风险。

• DOI: 10.1101/2023.04.21.23288938
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Talyansky,Seth;Guen,YannLe;Kasireddy,Nandita;Belloy,MichaelE;Greicius,MichaelD
• 通讯作者: Greicius,MichaelD

APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.

• DOI: 10.1186/s40478-023-01626-6
• 发表时间: 2023-09-12
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1