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- Title
Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.
- Authors
Thomsen, Soren K.; Ceroni, Alessandro; de Bunt, Martijn van; Burrows, Carla; Barrett, Amy; Scharfmann, Raphael; Ebner, Daniel; McCarthy, Mark I.; Gloyn, Anna L.; van de Bunt, Martijn
- 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 β-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 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, 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 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.
- Subjects
GENETICS of type 2 diabetes; TYPE 2 diabetes risk factors; ISLANDS of Langerhans; GENE silencing; CELL proliferation; PROTEIN metabolism; CELL lines; DISEASE susceptibility; INSULIN; LONGITUDINAL method; TYPE 2 diabetes; PROTEINS; RESEARCH funding; SEQUENCE analysis
- Publication
Diabetes, 2016, Vol 65, Issue 12, p3805
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-0361