Fig. 4: Trans- and cis-risk variant enrichment at histone-acetylated marks on experimentally stimulated immune cells in the Soskic immune stimulation dataset.
a Bar plots show enrichment of genetic risk for each condition at active promoters/enhancers (H3K27ac marks) in sorted and unstimulated or ex vivo stimulated immune cell subsets: macrophages, naïve CD4+ (helper) T cells and memory CD4+ T cells, assayed at both early and late timepoints after stimulation with one of several different cytokine cocktails promoting differentiation to different T cell states (as shown in row labels). CHEERS was used to detect enrichment of risk loci at cell-type specific H3K27ac peaks (see Methods). P-values are reported from a discrete uniform distribution (one-sided tests). The dotted black line marks the nominal significance threshold, P < 0.05; the solid black line marks the Bonferroni-corrected significance threshold, PBonferroni < 0.05. Note differing x-axis scales. Results for other disorders are shown in Supplementary Fig. 6. b Venn diagrams show counts of variant-peak overlaps shared between disorders and unique to each disorder. For an upset plot of peak overlaps across all disorders, see Supplementary Fig. 7b. c All Soskic immune stimulation dataset peaks overlapped by risk variants for major depressive disorder (MDD). Each row corresponds to an H3K27ac peak overlapping a risk variant for MDD; each column corresponds to a different cytokine-induced cell state, ordered and colored as in Fig. 4a (see legend). The blue fill shade represents how specific each peak is to each cell state (specificity rank of each peak normalized to the mean specificity rank of all peaks). Only 9 of the 108 MDD-associated H3K27ac immune peaks also overlap BMI risk variants. d For peaks which were both highly specific to T cells (including both unstimulated and stimulated cells) and overlapped by trans-risk variants, nearest genes were identified and tested for enrichment for curated biological pathways (GO and Reactome) using a one-sided hypergeometric test. Only the 10 most significant pathways are shown (all FDR < 0.05). Fill colour indicates gene ratio (number of test genes in the pathway/total number of test genes). See Supplementary Fig. 8 for results for cis-diagnostic risks. GO gene ontology, BMI body mass index.
