美国麻省理工学院和哈佛大学的布罗德研究所Alkes L. Price，Martin Jinye Zhang，美国加州大学Bogdan Pasaniuc和Kangcheng Hou共同合作近期取得重要工作进展，他们利用单细胞RNA-seq数据进行多基因富集区分单个细胞的疾病关联性。相关工作2022年9月1日在线发表于《自然—遗传学》杂志上。

研究人员引入了单细胞疾病相关性评分（scDRS），这是一种在单细胞分辨率下将scRNA-seq 与多基因疾病风险联系起来的方法，与带注释的细胞类型无关。scDRS可识别全基因组关联研究（GWAS）中涉及的疾病相关基因过度表达的细胞。研究人员将scDRS应用于31个组织/器官的74种疾病和130万个单细胞基因表达谱。

细胞类型水平的结果广泛概括了已知的细胞类型-疾病关联。单个细胞水平的结果确定了未被现有细胞类型标记捕获的疾病相关细胞亚群，包括与炎症性肠病相关的T细胞亚群，其部分特征在于它们的效应样状态；与精神分裂症相关的神经元亚群，部分特征在于它们的空间位置；以及与甘油三酯水平相关的肝细胞亚群，部分特征在于其较高的倍体水平。表达与跨细胞的scDRS评分相关的基因（反映与GWAS疾病相关基因的共表达）强烈富集了金标准药物靶点和孟德尔疾病基因。

据介绍，单细胞RNA测序（scRNA-seq）为疾病的病理学和细胞起源提供了独特的见解。

附：英文原文

Title: Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data

Author: Zhang, Martin Jinye, Hou, Kangcheng, Dey, Kushal K., Sakaue, Saori, Jagadeesh, Karthik A., Weinand, Kathryn, Taychameekiatchai, Aris, Rao, Poorvi, Pisco, Angela Oliveira, Zou, James, Wang, Bruce, Gandal, Michael, Raychaudhuri, Soumya, Pasaniuc, Bogdan, Price, Alkes L.

Issue&Volume: 2022-09-01

Abstract: Single-cell RNA sequencing (scRNA-seq) provides unique insights into the pathology and cellular origin of disease. We introduce single-cell disease relevance score (scDRS), an approach that links scRNA-seq with polygenic disease risk at single-cell resolution, independent of annotated cell types. scDRS identifies cells exhibiting excess expression across disease-associated genes implicated by genome-wide association studies (GWASs). We applied scDRS to 74 diseases/traits and 1.3 million single-cell gene-expression profiles across 31 tissues/organs. Cell-type-level results broadly recapitulated known cell-type–disease associations. Individual-cell-level results identified subpopulations of disease-associated cells not captured by existing cell-type labels, including T cell subpopulations associated with inflammatory bowel disease, partially characterized by their effector-like states; neuron subpopulations associated with schizophrenia, partially characterized by their spatial locations; and hepatocyte subpopulations associated with triglyceride levels, partially characterized by their higher ploidy levels. Genes whose expression was correlated with the scDRS score across cells (reflecting coexpression with GWAS disease-associated genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.

DOI: 10.1038/s41588-022-01167-z

Source: https://www.nature.com/articles/s41588-022-01167-z