Identification of C2CD4A as a human diabetes susceptibility gene with a role in β cell insulin secretion

Fine mapping and validation of genes causing beta cell failure from susceptibility loci identified in type 2 diabetes genome-wide association studies (GWAS) poses a significant challenge. The VPS13C-C2CD4A-C2CD4B locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1 is involved in the pathogenesis of beta cell dysfunction, but its link to human diabetes GWAS has not been explored. Here we generated a genome-wide map of FoxO1 super-enhancers in chemically identified beta cells using 2-photon live-cell imaging to monitor FoxO1 localization. When parsed against human superenhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved superenhancer in C2CD4A, a gene encoding a beta cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in beta cells of mice phenocopied the metabolic abnormalities of human carriers of C2CD4A-linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2CD4A regulates glycolytic genes, and notably represses key beta cell "disallowed" genes, such as lactate dehydrogenase A. We propose that C2CD4A is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.