Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.
2016
Most
genetic associationsignals 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 isletdysfunction. Systematically characterizing the role of regional transcripts in β-cell function could identify the underlying disease-causing genes, but large-scale studies in human
cellular modelshave previously been impractical. We developed a robust and scalable strategy based on arrayed gene silencing in the human β-cell line EndoC-βH1. 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 β-cell
function,
pointingto possible causal mechanisms at 37 disease-associated loci. The results showed a strong enrichment for genes implicated in
monogenicdiabetes. Selected effects were validated in a follow-up study, including several genes (ARL15, ZMIZ1, and THADA) with previously unknown or poorly described roles in β-cell biology. We have demonstrated the feasibility of systematic functional screening in a human β-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.
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