摘要
Most genetic association signals for type 2 diabetes risk are located in noncoding regions of the genome, hindering translation into molecular mechanisms. Physiological studies have shown a majority of disease-associated variants to exert their effects through pancreatic islet dysfunction. Systematically characterizing the role of regional transcripts in beta-cell function could identify the underlying disease-causing genes, but large-scale studies in human cellular models have previously been impractical. We developed a robust and scalable strategy based on arrayed gene silencing in the human beta-cell line EndoC-beta H1. In a screen of 300 positional candidates selected from 75 type 2 diabetes regions, each gene was assayed for effects on multiple disease-relevant phenotypes, including insulin secretion and cellular proliferation. We identified a total of 45 genes involved in beta-cell function, pointing to possible causal mechanisms at 37 disease associated loci. The results showed a strong enrichment for genes implicated in monogenic diabetes. Selected effects were validated in a follow-up study, including several genes (ARL15, ZM1Z1, and THADA) with previously unknown or poorly described roles in beta-cell biology. We have demonstrated the feasibility of systematic functional screening in a human beta-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.
- 出版日期2016-12