Extended Data Fig. 6: (related to Fig. 3). WGCNA emphasizes α and islet cell gene modules associated with donor and islet traits as well as those enriched in GWAS loci.

(a-d) Though α cell modules showed weaker correlations to donor and functional traits than did β cell modules, several modules were significantly enriched for cilia-related genes (a) and α08 was also enriched for α cell genes differentially expressed in T2D α cells (b). Both α08 and α16 significantly inversely correlated with epinephrine-mediated glucagon secretion and were closely related across functional parameters (c). Module α08 showed significant enrichment for T2D GWAS variants (d). See also Supplementary Fig. 4b. (e-g) Several islet modules showed notable enrichment for immune- and matrisome-related genes (e). Module i25 correlated positively with T2D status (f) and inversely with basal insulin secretion and GSIS, while i26 correlated inversely with KCl-mediated insulin secretion (g). See also Supplementary Fig. 4c. Panels a and e show module eigengenes clustered by similarity and relative enrichment of curated gene lists (see also Supplementary Table 5). Panels b and f provide correlation to donor characteristics, enrichment of differentially expressed (DE) genes, and total number of genes per module (^• P < 0.05; * P < 0.01). Modules of interest highlighted (b: red, f: blue). Panels c and g show module correlation to α and β cell function (Fig. 1); significant associations highlighted (yellow). For islets (g), modules were correlated to both insulin and glucagon secretion (G + IBMX, 16.7 mM glucose with 100 μM isobutylmethylxanthine; 16.7 G, 16.7 mM glucose; 16.7 G 1°, first phase; 16.7 G 2°, second phase; 1.7 G+Epi, 1.7 mM glucose and 1 μM epinephrine; KCl, 20 mM potassium chloride). Panel d shows α cell module enrichment for GWAS traits (FIns, fasting insulin; 2hGlu, 2-hour glucose; FGlu, fasting glucose; * FDR < 0.01). Panels a, e, b and f (DE genes): two-tailed Fisher test adjusted for multiple comparisons; panels c, g, b and f (donor traits): t-test, unadjusted, using Spearman correlations (see Methods for additional details); panel d: enrichment using GARFIELD³⁷.