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: 10370810
• 负责人: Aliza Pham Wingo
• 金额: $ 76.39万
• 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/10370810
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease risk; 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; 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; Time; Transcript; Variant; Woman; Work; base; biobank; biological sex; brain tissue; case control; causal variant; cost; disorder risk; effective therapy; genetic variant; genome wide association study; high risk; improved; insight; interest; mRNA Expression; men; novel; novel strategies; protein expression; sex; statistics; transcription factor; transcriptome; transcriptomics

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.

阿尔茨海默病 (AD) 影响着全球 3500 万人。但目前尚无有效治疗方法 减缓或阻止 AD 潜在的神经变性。引人注目的是，女性受到 AD 的影响大约是女性的两倍 就像男人一样。为什么女性更容易受到 AD 的影响尚不清楚。 在这里，我们假设生物性别和大脑基因表达之间存在相互作用 女性患 AD 的风险更高。这个假设建立在我们研究遗传的工作的基础上 控制人脑中的基因表达。在这些研究中，我们已经确定了遗传位点 与人脑转录本和蛋白质水平的基因表达变化有关。识别 与大脑基因表达自然变异相关的遗传位点对于解决遗传问题非常有用 通过全基因组关联研究 (GWAS) 识别出与特定因果转录本和蛋白质相关的信号。我们 已成功使用脑基因转录本和蛋白质表达结果与 GWAS 结果来识别 AD（Wingo 等人，Nat Genet，2021）和抑郁症（Wingo 等人，Nat Neurosci，2021）的新型蛋白质。这些 分析揭示了遗传风险的原因，这可能是最重要的早期风险之一 疾病的促成因素，这使得它们与解决特定性别的疾病风险高度相关。 为了检验我们的假设，我们将首先对转录本和性别特异性大脑表达进行分析 蛋白质（目标 1）。为此，我们将利用现有的大脑转录本和生成的蛋白质表达数据 通过国家资源，我们提出了一种新的方法来经济有效地增加蛋白质组的深度 提高力量。我们期望为大脑转录本生成性别特异性数量性状基因座（QTL）（N=1655， 61% 女性）和蛋白质（N=1584，66% 女性），然后对每个基因进行测试以寻找证据 与性的互动。这些结果可能会引起神经科学和遗传学的普遍兴趣 社区，数据和结果将广泛提供给科学界。在目标 2 中，我们 我们将进行针对 AD 的性别特异性 GWAS，我们将识别与性别相互作用的遗传变异。为此， 我们将使用 1) 美国研究参与者的 AD 病例对照状态进行性别分层 GWAS (N=27,580)，2) 来自英国生物银行 (N=431,000) 的参与者的 AD 代理病例对照，以及 iii) 元- 分析 1 和 2。在目标 3 中，我们将识别导致 AD 发病机制的大脑转录本和蛋白质， 分别针对男性或女性。为此，我们将性别特异性大脑 QTL 与 性别特异性 GWAS 结果可分别解析女性和男性蛋白质的 GWAS 信号。对于AD 具有性别相互作用证据的遗传信号，我们将测试性别特异性基因表达是否说明 使用因果推理方法（例如孟德尔方法）了解性别之间 AD 风险的差异 随机化）。该项目的发现很可能为性提供新颖的机制见解 AD 的差异以及 AD 进一步性别特异性机制和治疗研究的有希望的新靶点。