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

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）’，是复杂疾病研究的核心挑战。针对2型糖尿病（type 2 diabetes），目前已发现数百个独立信号可调控疾病风险，其中多数通过胰岛细胞功能障碍发挥作用。本研究在人胰腺β细胞中开展了全基因组混合CRISPR功能丧失筛选，以鉴定调控胰岛素含量的基因。本研究揭示了细胞筛选可如何补充现有多组学研究体系，从而加速全基因组关联研究（Genome-Wide Association Study, GWAS）位点处的生物学推断与转化推断进程。