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Diabetes

Identifying type 2 diabetes risk genes by β-cell CRISPR screening

Nature Genetics volume 55, pages 4–5 (2023)Cite this article

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A major challenge in human genetics is the prioritization of causal genes in common complex diseases. A genome-wide CRISPR screen for intracellular insulin content in a human β-cell line has now identified a new candidate gene for type 2 diabetes, demonstrating the utility of this screening approach in β-cells.

Using the EndoC-βH1 human β-cell line4, the authors measured intracellular insulin content using fluorescence-activated cell sorting. After validating the readout to detect genes known to be involved in insulin content (for example, INS itself and PAM), two independent screen replicates were performed, targeting 18,053 genes with four single guide RNAs each. The top and bottom 10% of cells, as measured by insulin content, were selected and sequenced to determine the single guide RNA responsible. A stringent set of criteria was used to evaluate the screening results, resulting in 580 genes passing the significance threshold. Several genes known to regulate β-cell function were identified as screening hits, as were genes involved in monogenic diabetes. Network analysis of the hits, using GO (gene ontology) terms, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and STRING (search tool for the retrieval of interacting genes/proteins) analysis, revealed a set of common modules, including proteolysis and autophagy, mitochondrial ATP synthesis, vesicle trafficking and exocytosis, G-protein-coupled receptor signaling and lipid metabolism. The authors then looked at the overlap between screening hits and 336 candidate T2D genes, which were determined by querying curated gene predictions in the Type 2 Diabetes Knowledge Portal (https://go.nature.com/3AZYZjE). Twenty genes were members of both sets, yielding predicted effector genes for further study.

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Fig. 1: Approach to identify genes important for insulin content in β-cells.

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  1. Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA

    Bridget K. Wagner

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  1. Bridget K. Wagner
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Correspondence to Bridget K. Wagner.

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Wagner, B.K. Identifying type 2 diabetes risk genes by β-cell CRISPR screening. Nat Genet 55, 4–5 (2023). https://doi.org/10.1038/s41588-022-01269-8

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