Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.

ABSTRACT: 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 ?-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 ?-cell line EndoC-?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 ?-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, ZMIZ1, and THADA) with previously unknown or poorly described roles in ?-cell biology. We have demonstrated the feasibility of systematic functional screening in a human ?-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.

SUBMITTER: Thomsen SK 

PROVIDER: S-EPMC5402869 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature