247-OR: Variant-to-Gene-Mapping Analyses Reveal a Role for Pancreatic Islet Cells in Conferring Genetic Susceptibility to Sleep-Related Traits

Abstract

Altered glucose metabolism observed in sleep dysregulation has been reported to contribute to obesity and type 2 diabetes (T2D) risk. We elected to investigate if known sleep loci exert any of their effect in the pancreatic alpha and beta-cell setting. To establish genetic commonalities between sleep and metabolic disorders, we conducted linkage disequilibrium (LD) genetic correlation analyses with publicly available GWAS summary statistics for 4 sleep-associated traits (insomnia, chronotype, short and long sleep), T2D and obesity. Insomnia was significantly correlated with both T2D (genetic correlation (rg)=0.2; P=2.4x10-11) and obesity (rg=0.13; P=0.0021), as was short sleep (T2D, rg=0.2; P=1.8x10-10; obesity, rg=0.22; and P=5.1x10-7) and long sleep (T2D, rg=0.23; P=3.1x10-10; obesity rg=0.09; P=0.019). Chronotype was significantly correlated with T2D only (rg=0.05; P=0.038). Using partitioned LD score regression we then intersected summary statistics with our ATAC-seq and high-resolution promoter-focused Capture C data to assess enrichment of sleep trait SNPs within promoter-interacting open chromatin regions in both the human beta-cell line, EndoC-BH1, and sorted human alpha-cells. EndoC-BH1 was highly significantly enriched for chronotype loci (P=2.2x10-7). Furthermore there was significant enrichment for insomnia (P=0.01) and short sleep (P=0.017). The alpha-cells were also significantly enriched for chronotype (P=0.0016), insomnia (P=0.0076), short sleep (P=0.022), along with long sleep (P=0.034). Motivated by these observations, subsequent variant-to-gene mapping implicated 32, 37 and 6 putative effector genes for insomnia, chronotype and short sleep, respectively, in EndoC-BH1. For alpha-cells, 55, 54, 10 and 5 genes were implicated for insomnia, chronotype, short and long sleep, respectively. Our data suggest that a subset of sleep-related loci confer their effects via cells in pancreatic islets. Disclosure C. Lasconi: None. M. C. Pahl: None. J. A. Pippin: None. C. Su: None. M. Johnson: None. A. Chesi: None. A. D. Wells: None. K. H. Kaestner: None. S. F. A. Grant: None. Funding National Institutes of Health (UM1DK126194)