RT Journal Article
SR Electronic
T1 Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 3805
OP 3811
DO 10.2337/db16-0361
VO 65
IS 12
A1 Thomsen, Soren K.
A1 Ceroni, Alessandro
A1 van de Bunt, Martijn
A1 Burrows, Carla
A1 Barrett, Amy
A1 Scharfmann, Raphael
A1 Ebner, Daniel
A1 McCarthy, Mark I.
A1 Gloyn, Anna L.
YR 2016
UL http://diabetes.diabetesjournals.org/content/65/12/3805.abstract
AB 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.