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）影响全世界3500万人。然而，没有有效的治疗方法， 来减缓或停止AD的潜在神经变性。值得注意的是，女性受AD影响的比例约为男性的两倍。 就像男人一样。为什么女性不成比例地受到AD的影响还不清楚。 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， 使女性更容易患上AD。这一假设建立在我们对遗传学的研究基础上。 控制人类大脑中的基因表达。在这些研究中，我们已经确定了遗传位点， 与人类大脑中转录本和蛋白质水平上的基因表达变异有关。识别 与大脑基因表达的自然变异相关的遗传位点对于解决遗传问题是非常有用的。 通过全基因组关联研究（GWAS）鉴定的信号与特定的因果转录本和蛋白质有关。我们 已经成功地将脑基因转录和蛋白质表达结果与GWAS结果结合起来， 用于AD（Wingo等人，Nat Genet，2021）和抑郁症（Wingo等人，Nat Neurosci，2021）的新蛋白。这些 分析暗示了遗传风险的原因，这可能是最重要的早期风险之一。 这使得它们与解决性别特异性疾病风险高度相关。 为了验证我们的假设，我们将首先对转录本进行性别特异性的大脑表达分析， 蛋白质（Aim 1）。为了做到这一点，我们将利用现有的大脑转录本和蛋白质表达数据生成 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， 提高功率。我们期望产生脑转录物的性别特异性数量性状基因座（QTL）（N=1655， 61%的女性）和蛋白质（N=1584，66%的女性），然后对每个基因进行检测， 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， 将进行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。要执行此操作， 我们将使用1）来自美国研究的受试者的AD病例对照状态进行性别分层GWAS （N= 27，580），2）来自英国生物样本库的参与者中的AD-代理病例对照（N= 431，000），以及iii）一项Meta分析， 分析1和2。在目标3中，我们将鉴定有助于AD发病机制的脑转录物和蛋白质， 分别针对男性和女性。为了做到这一点，我们将性别特异性脑QTL与 性别特异性GWAS结果，分别将GWAS信号解析为女性和男性的蛋白质。的AD 遗传信号与性别相互作用的证据，我们将测试是否性别特异性基因表达帐户 对于使用因果推断方法的性别之间AD风险的差异（例如，孟德尔 随机化）。这个项目的发现很有可能为性行为提供新的机制性见解 AD的差异和有前途的新目标，进一步性别特异性机制和治疗研究的AD。