Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits

We investigated the potential role of sleep-trait associated genetic loci in conferring a degree of their effect via pancreatic alpha- and beta-cells, given that both sleep disturbances and metabolic disorders, including type 2 diabetes and obesity, involve polygenic contributions and complex interactions. We determined genetic commonalities between sleep and metabolic disorders, conducting linkage disequilibrium genetic correlation analyses with publicly available GWAS summary statistics. Then we investigated possible enrichment of sleep-trait associated SNPs in promoter-interacting open chromatin regions within alpha- and beta-cells, intersecting public GWAS reports with our own ATAC-seq and high-resolution promoter-focused Capture C data generated from both sorted human alpha-cells and an established human beta-cell line (EndoC-beta H1). Finally, we identified putative effector genes physically interacting with sleep-trait associated variants in alpha- and EndoC-beta H1cells running variant-to-gene mapping and establish pathways in which these genes are significantly involved. We observed that insomnia, short and long sleep-but not morningness-were significantly correlated with type 2 diabetes, obesity and other metabolic traits. Both the EndoC-beta H1 and alpha-cells were enriched for insomnia loci (p = .01; p = .0076), short sleep loci (p = .017; p = .022) and morningness loci (p = 2.2 x 10(-7); p = .0016), while the alpha-cells were also enriched for long sleep loci (p = .034). Utilizing our promoter contact data, we identified 63 putative effector genes in EndoC-beta H1 and 76 putative effector genes in alpha-cells, with these genes showing significant enrichment for organonitrogen and organophosphate biosynthesis, phosphatidylinositol and phosphorylation, intracellular transport and signaling, stress responses and cell differentiation. Our data suggest that a subset of sleep-related loci confer their effects via cells in pancreatic islets.