Integrative Genomic Approaches for Understanding Sex Differences in Alzheimer's Disease

项目摘要 女性占美国所有阿尔茨海默病(AD)病例的近三分之二，这些 差异可能是由于不同的遗传和环境影响造成的 性别。虽然几项候选基因研究已经确定了性别特有的关联，但没有大规模的基因组- 已经进行了广泛的、特定性别的阿尔茨海默病关联分析。此外，功能基础 性别特有的遗传关联以及它们与表达和表观遗传变异的关系仍然是 很大程度上是未知的。我们假设，多种遗传、表观遗传和基因表达的变化在 以性别特有的方式解释AD患病率中至少部分性别差异。为此，我们提出了新的 性别中DNA变异、基因表达、剪接和DNA甲基化的综合分析策略- Aware框架，这将使我们能够优先考虑最具监管潜力的变体，并提供 对阿尔茨海默病性别差异的生物学机制的更多洞察。为了实现这些目标，我们将 利用AD中几个联盟研究的现有大规模遗传数据，以及表达和 阿尔茨海默病患者和正常人脑组织甲基化数据。我们提出了以下具体建议 目的：1)通过关联和遗传关联评估AD的性别特异性遗传结构 分析；2)进行转录组范围的关联分析，以确定与AD相关的性别特异性变化； 3)进行以区域为中心的分析，以确定导致AD的性别特异性DNA甲基化变化；以及 4)通过综合分析确定性别特异性基因座的优先顺序，并制定性别特异性多基因AD的风险评分。 该项目的成功完成将带来第一个大规模的针对性别的全基因组AD分析。 它还将为基因组和表观基因组数据集的全面和综合分析提供一个范例 在一个性别感知的框架中。通过集中分析多种类型的组学数据，我们的研究将 对性别差异背后的遗传和表观遗传程序提供更完整的理解 AD，这将导致更好的预防、诊断和个体化治疗策略。

Project Summary Women make up nearly two-thirds of all Alzheimer's disease (AD) cases in the United States and these differences are likely due to contributions from differential genetic and environmental effects between the sexes. While several candidate gene studies have identified sex-specific associations, no large-scale, genome- wide, sex-specific association analysis of AD has been conducted. Furthermore, the functional underpinnings of sex-specific genetic associations and how they relate to expression and epigenetic variations, are still largely unknown. We hypothesize that multiple genetic, epigenetic and gene-expression changes operate in a sex-specific manner to explain at least part of the sex disparity in AD prevalence. To this end, we propose new strategies for integrative analysis of DNA variants, gene expression, splicing and DNA methylation in a sex- aware framework, which will allow us to prioritize variants with the most regulatory potential and provide additional insight into the biological mechanisms of sex differences in AD. To accomplish these goals we will leverage existing large-scale genetic data from several consortia studies in AD, as well as expression and methylation data from brain tissue of AD cases and healthy individuals. We propose the following specific aims: 1) Evaluate the sex-specific genetic architecture of AD through association and genetic correlation analysis; 2) Conduct transcriptome-wide association analyses to identify sex-specific changes relevant to AD; 3) Conduct region-centric analysis to identify sex-specific DNA methylation changes that contribute to AD; and 4) Prioritize sex-specific loci and develop sex-specific polygenic risk scores for AD through integrative analysis. Successful completion of this project will deliver the first large scale sex-specific genome-wide analysis of AD. It will also provide a paradigm for comprehensive and integrative analysis of genomic and epigenomic datasets in a sex-aware framework. By focusing on integrative analysis of multiple types of `omics data, our study will provide a more complete understanding of the genetic and epigenetic programs underlying sex differences in AD, which will lead to better prevention, diagnosis and individualized treatment strategies.