Figure 3. Enrichment of islet accessible chromatin for diabetes and fasting glycemia.

(a) Stratified LD score regression enrichment z-scores for diabetes-related quantitative endophenotypes (top), type 1 and 2 diabetes (middle), and control traits (bottom) for islet cell types. **FDR<0.01 *FDR<0.1. (b) Single cell enrichment z-scores for fasting glucose level (FG) and T2D projected onto UMAP coordinates (left), enrichment per cell type (middle panels), and beta cell enrichment split into 10 trajectory bins (right). Boxplot center line, limits, and whiskers represent median, quartiles, and 1.5 interquartile range respectively. (c) Enrichment (estimate ± 95% CI by fgwas) of variants at loci associated with both T2D and FG (T2D/FG) within beta cell accessible chromatin. (d) Candidate causal T2D variant rs11708067 overlaps an enhancer active in INS^high beta cells at the ADCY5 locus, consistent with beta cell enrichment patterns for T2D/FG loci. (e) Enrichment (estimate ± 95% CI by fgwas) of variants at T2D loci in accessible chromatin for non-beta endocrine cells after removing beta accessible chromatin. (f) Candidate causal T2D variant rs1111875 overlaps a delta cell-specific site at the HHEX locus. (g) Correlation between single cell FG and TF motif enrichments across all 14.2k cells (left) and 7.2k beta cells (right). Across all cells, FG has positive correlations with beta-enriched TF families such as PDX, NKX6 and PAX. Within beta cells, FG has positive correlations with INS^high beta-enriched TF families such as RFX, MAF/NRL, and FOXA. (h) Enrichment (effect±SE) of FG-associated variants directly overlapping sequence motifs for those either positively or negatively correlated with FG in beta cells.