Integrative modelling of single-cell data to elucidate the genetic architecture of complex disease

项目总结/摘要 利用全基因组关联研究（GWAS）来了解疾病已被证明具有挑战性，因为 潜在的生物学机制通常很难被大块组织捕获。单细胞研究进展 测序导致了跨越多种模式，背景和个人的数据洪流，这提供了一个 前所未有的机会，以高分辨率了解疾病生物学。我们假设罚款- 由单细胞数据捕获的规模细胞背景将有效地解释疾病遗传性和精细化。 映射疾病机制。然而，目前将单细胞数据与GWAS集成的方法主要是 依赖于为批量测序开发的现成方法，这掩盖了丰富的表型多样性。 存在于典型细胞类型内和跨典型细胞类型的单个细胞中。稀疏和高度可变的性质， 单细胞数据还对稳健地鉴定单细胞数量性状基因座（QTL）提出了挑战。 单单元数据的规模和复杂性不断增加，强调了可扩展的集成 建模在这里，我们提出了一个5年的研究计划，以开发新的方法，整合单细胞 通过对现有批量方法无法捕获的复杂细胞表型进行建模，获得GWAS数据。我们 该提案将确定新的疾病相关细胞状态;利用多种单细胞模式来精细映射 疾病变体及其靶基因;并发现与疾病相关的新的单细胞QTL。我们 具体目标是：目标1：利用单细胞表观遗传数据来确定疾病的遗传成分; 目标2：利用单细胞数据精细绘制疾病变体及其机制;目标3：定义 使用群体规模scRNA-seq的疾病变体的调节作用。虽然我们提出的方法是 广泛适用于常见疾病，我们将以免疫相关特征为基准， 神经精神特征，我们已经广泛研究了大量数据集在出版的工作，我们在哪里， 现在已经聚集了大量相关的单细胞数据集。我们的合作有多个 优势：我们专注于跨多个单细胞模式的功能数据集成;我们广泛的统计分析 和计算专业知识;以及我们在常见疾病方面广泛的、数据驱动的出版记录。

PROJECT SUMMARY/ABSTRACT Leveraging Genome Wide Association Studies (GWAS) to understand disease has proven challenging, as the underlying biological mechanisms are often poorly captured by bulk tissues. Recent advances in single-cell sequencing have led to a torrent of data across multiple modalities, contexts, and individuals, which provide an unprecedented opportunity to understand disease biology at high resolution. We hypothesize that the fine- scale cellular contexts captured by single-cell data will be effective at explaining disease heritability and fine- mapping disease mechanisms. However, current approaches to integrate single-cell data with GWAS largely rely on off-the-shelf approaches developed for bulk sequencing, which obscure the rich phenotypic diversity present in individual cells within and across canonical cell types. The sparse and highly variable nature of single-cell data has additionally posed challenges for robustly identifying single-cell quantitative trait loci (QTL). Single-cell data continues to increase in size and complexity, emphasizing the need for scalable integrative modeling. Here, we propose a 5 year research plan to develop novel approaches for integrating single-cell data with GWAS by modeling complex cellular phenotypes not captured by existing bulk approaches. Our proposal will identify novel disease-relevant cell states; leverage multiple single-cell modalities to fine-map disease variants and their target genes; and discover novel single-cell QTLs associated with disease. Our specific aims are: Aim 1: Leveraging single-cell epigenetic data to identify heritable components of disease; Aim 2: Leveraging single-cell data to fine-map disease variants and their mechanisms; Aim 3: Defining the regulatory effects of disease variants using population-scale scRNA-seq. While our proposed approaches are broadly applicable to common diseases, we will benchmark them on immune-related traits and neuropsychiatric traits which we have studied extensively with bulk datasets in published work and where we have now aggregated a large collection of relevant single-cell datasets. Our collaboration has multiple strengths: our focus on functional data integration across multiple single-cell modalities; our broad statistical and computational expertise; and our extensive, data-driven publication record on common disease.