Integrative genomic, transcriptomic, and proteomic analyses to investigate sex-specific differences in Alzheimer's Disease

综合基因组、转录组和蛋白质组分析研究阿尔茨海默病的性别特异性差异

• 批准号: 10581657
• 负责人: Aliza Pham Wingo
• 金额: $ 75.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581657
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease risk; Alzheimer' s disease test; American; Biological; Brain; Communities; Community Health; DNA Resequencing; Data; Dementia; Diagnosis; Disease; Etiology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic Variation; Genets; Genomics; Heritability; Human; Individual; Inherited; International; Maps; Mediating; Mendelian randomization; Mental Depression; Meta-Analysis; Molecular; Nerve Degeneration; Neurosciences; Participant; Pathogenesis; Persons; Proteins; Proteome; Proteomics; Proxy; Public Health; Publishing; Quantitative Trait Loci; Regulation; Resources; Role; Science; Sex Differences; Signal Transduction; Site; Source; Testing; Therapeutic Studies; Transcript; Variant; Woman; Work; biobank; biological sex; brain tissue; case control; causal variant; cost; disorder risk; effective therapy; genetic variant; genome wide association study; genome-wide analysis; high risk; improved; insight; interest; mRNA Expression; men; novel; novel strategies; protein expression; sex; statistics; transcription factor; transcriptome; transcriptomics; web site

Alzheimer's disease (AD) affects 35 million people worldwide. However, there is no effective treatments to slow or halt the underlying neurodegeneration of AD. Strikingly, women are affected by AD about twice as much as men. Why women are disproportionately affected by AD is not well understood. Here, we hypothesize that there is an interaction between biological sex and brain gene expression that predisposes women to have a higher risk for AD. This hypothesis builds on our work investigating the genetic control of gene expression in the human brain. In those studies, we have identified genetic sites that are associated with variation in gene expression at the transcript and protein level in the human brain. Identifying genetic sites associated with natural variation in brain gene expression are incredibly useful to resolve genetic signals identified by genome-wide association study (GWAS) to specific causal transcripts and proteins. We have successfully used brain gene transcript and protein expression results with GWAS results to identify novel proteins for AD (Wingo et al, Nat Genet, 2021) and depression (Wingo et al, Nat Neurosci, 2021). These analyses implicate the causes of inherited genetic risk, which are presumably among the most important early contributors to disease, which make them highly relevant to resolving sex-specific disease risk. To test our hypothesis, we will first perform a sex-specific brain expression analysis for transcripts and proteins (Aim 1). To do this, we will leverage existing brain transcripts and protein expression data generated by national resources, and we propose a novel approach to cost-effectively increase the depth of proteomes to improve power. We expect to generate sex-specific quantitative trait loci (QTL) for brain transcripts (N=1655, 61% women) and proteins (N=1584, 66% women), and each gene will then be tested for evidence of interaction with sex. These results are likely to be of general interest to the neuroscience and genetics communities, and the data and results will be made widely available to the science community. In Aim 2, we will perform a sex-specific GWAS of AD, and we will identify genetic variants that interact with sex. To do this, we will perform sex-stratified GWAS using 1) case-control status for AD in participants from US studies (N=27,580), 2) AD-proxy case-control in participants from the UK Biobank (N=431,000), and iii) a meta- analysis of 1 and 2. In Aim 3, we will identify brain transcripts and proteins contributing to AD pathogenesis that are specific to men or women, respectively. To do this, we will integrate the sex-specific brain QTLs with the sex-specific GWAS results to resolve GWAS signals to proteins for women and men, separately. For AD genetic signals with evidence for sex interaction, we will test whether sex-specific gene expression accounts for the differences in AD risk between the sexes using causal inference approaches (e.g., Mendelian randomization). Findings from this project are highly likely to provide novel mechanistic insights into sex differences in AD and promising new targets for further sex-specific mechanistic and therapeutic studies of AD.

阿尔茨海默氏病（AD）影响了全球3500万人。但是，没有有效的治疗 慢慢或停止AD的基本神经变性。令人惊讶的是，女性受广告影响大约两倍 和男人一样。为什么妇女受到广告的影响不成比例的影响不太了解。 在这里，我们假设生物性别和脑基因表达之间存在相互作用， 使妇女容易出现较高的AD风险。这个假设以我们研究遗传的工作为基础 控制人脑基因表达。在这些研究中，我们已经确定了 与人脑的转录本和蛋白质水平的基因表达变异有关。识别 与脑基因表达中自然变异相关的遗传位点对于解决遗传非常有用 通过全基因组关联研究（GWAS）鉴定的特定因果转录本和蛋白质的信号。我们 已经成功使用了脑基因转录本和蛋白质表达结果，其结果是鉴定 AD的新型蛋白质（Wingo等，Nat Genet，2021）和抑郁症（Wingo等，Nat Neurosci，2021）。这些 分析暗示了遗传遗传风险的原因，遗传风险大概是最重要的早期之一 疾病的贡献者，这使其与解决性别特异性疾病的风险高度相关。 为了检验我们的假设，我们将首先对成绩单进行性别特异性的大脑表达分析和 蛋白质（目标1）。为此，我们将利用现有的大脑成绩单和蛋白质表达数据生成 通过国家资源，我们提出了一种新颖的方法，以成本效益将蛋白质组的深度提高到 提高功率。我们期望为脑转录本生成性别特异性的定量特质基因座（QTL）（n = 1655， 61％的女性）和蛋白质（n = 1584，66％女性），然后将测试每个基因的证据 与性互动。这些结果可能会引起神经科学和遗传学的普遍关注 社区以及数据和结果将广泛地为科学界提供。在AIM 2中，我们 将执行AD的性别特异性GWA，我们将确定与性相互作用的遗传变异。为此， 我们将使用1）在美国参与者中使用1）AD的病例对照状态进行性分层的GWA （n = 27,580），2）来自英国生物银行（n = 431,000）的参与者的Ad-Proxy病例对照，iii）a meta- 分析1和2。在AIM 3中，我们将确定有助于AD发病机理的脑转录本和蛋白质 分别针对男人或女人。为此，我们将将特定性别的大脑QTL与 性别特定的GWAS结果分别解决了男性和男性蛋白质的GWAS信号。对于广告 具有性相互作用证据的遗传信号，我们将测试性别特定基因表达 对于使用因果推理方法，性别之间的AD风险差异（例如Mendelian 随机化）。该项目的发现很可能为性提供新颖的机械见解 AD的差异以及有希望的新目标，用于进一步的性别特异性机理和AD治疗研究。