Program of Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America.
Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, Connecticut, United States of America.
PLoS Genet. 2023 Jul 31;19(7):e1010825. doi: 10.1371/journal.pgen.1010825. eCollection 2023 Jul.
Finding disease-relevant tissues and cell types can facilitate the identification and investigation of functional genes and variants. In particular, cell type proportions can serve as potential disease predictive biomarkers. In this manuscript, we introduce a novel statistical framework, cell-type Wide Association Study (cWAS), that integrates genetic data with transcriptomics data to identify cell types whose genetically regulated proportions (GRPs) are disease/trait-associated. On simulated and real GWAS data, cWAS showed good statistical power with newly identified significant GRP associations in disease-associated tissues. More specifically, GRPs of endothelial and myofibroblasts in lung tissue were associated with Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease, respectively. For breast cancer, the GRP of blood CD8+ T cells was negatively associated with breast cancer (BC) risk as well as survival. Overall, cWAS is a powerful tool to reveal cell types associated with complex diseases mediated by GRPs.
找到与疾病相关的组织和细胞类型可以促进功能基因和变异体的鉴定和研究。特别是，细胞类型比例可以作为潜在的疾病预测生物标志物。在本手稿中，我们介绍了一种新的统计框架，即细胞类型全基因组关联研究（cWAS），该框架将遗传数据与转录组学数据相结合，以识别其遗传调控比例（GRP）与疾病/特征相关的细胞类型。在模拟和真实的 GWAS 数据上，cWAS 显示出良好的统计功效，并在与疾病相关的组织中发现了新的显著的 GRP 关联。更具体地说，肺组织中的内皮细胞和肌成纤维细胞的 GRP 分别与特发性肺纤维化和慢性阻塞性肺疾病相关。对于乳腺癌，血液 CD8+T 细胞的 GRP 与乳腺癌（BC）风险以及生存呈负相关。总的来说，cWAS 是一种强大的工具，可以揭示由 GRP 介导的与复杂疾病相关的细胞类型。
