A genome-wide CRISPR screen identifies regulators of beta cell function involved in type 2 diabetes risk. Genome-wide CRISPR screen

Identifying the genes or “effector transcripts” responsible for mediating genetic association signals is a major challenge for complex disease. For type 2 diabetes, there are hundreds of independent signals exerting their effects on disease risk with many acting through pancreatic islet-cell dysfunction. We performed a genome-wide pooled CRISPR loss-of-function screen in human pancreatic beta cells to identify genes regulating insulin content. Our study highlights how cellular screens can augment existing multi-omic efforts to accelerate biological and translational inference at GWAS loci.

鉴定介导遗传关联信号的基因或‘效应转录本（effector transcripts）’，是复杂疾病研究领域的一项核心挑战。针对2型糖尿病而言，目前已发现数百个独立的遗传关联信号可影响疾病发病风险，其中多数信号通过胰岛细胞功能障碍发挥致病作用。我们在人类胰腺β细胞中开展了全基因组混合CRISPR功能丧失筛选，以筛选调控胰岛素含量的相关基因。本研究阐明了细胞筛选可如何赋能现有多组学研究，从而加速全基因组关联研究（Genome-Wide Association Study, GWAS）位点的生物学机制推断与转化应用进程。