Fig. 1: Trans-diagnostic risk enrichment at epigenetically active sites in brain tissue and, independently, in T cells.

a Enrichment of trans-diagnostic risk at active regulatory elements in 88 tissues from the Roadmap epigenomics consortium. P-values estimated by stratified linkage disequilibrium score regression (LDSC) analysis (see Methods) were used to test the null hypotheses (one-sided tests) that risk variants were not co-located with epigenetically activated sites more frequently than expected by chance, using the false discovery rate (FDR < 0.05; orange) to correct for multiple tests across N = 88 tissues. Tissues with nominally significant enrichment (P < 0.05, blue) are also shown for context. For results in all other tissues see Supplementary Fig. 1. b Validation of brain-conditioned LDSC modelling. As expected, when the LDSC model for enrichment of adult brain tissues was conditioned on the active regulatory annotations for fetal brain tissue (male and female), there was significant reduction in enrichment across all adult brain tissues (asterisks indicate one-sided two-sample Z-tests with P < 0.05). c Brain-conditioned analysis of enrichment of trans-diagnostic risk variants at active regulatory annotations in immune tissues. Probability of enrichment (log P scale) was estimated by both unconditioned LDSC modelling (left panel of bar chart; same data as in Fig. 1a but on a different x-axis range of log probabilities); and brain-conditioned LDSC modelling (right panel of bar chart), one-sided tests. Conditioning enrichment of immune cells on active regulatory annotations in all brain tissues did not significantly reduce enrichment for any immune tissue (all two-sample Z-tests had P > 0.05); but some T cell subsets were no longer significantly enriched at FDR = 5%; see Supplementary Fig. 2 for comparable results in all other tissues. d Enrichment of trans-diagnostic risk in enhancers, genic enhancers and active promoters in all immune subsets (LDSC, one-sided tests). Large tiles show results significant at FDR < 0.05, to correct for the 78 annotations tested; mid-sized tiles show results significant at P < 0.05. Tile fill indicates the P-value rank within each annotation across cell types. There was enrichment of trans-risk at both enhancers and promoters in multiple adaptive immune cell subsets. See Supplementary Data 1 for full statistics. PFC prefrontal cortex, HSC hematopoietic stem cell, PMA-I phorbol-myristate-acetate and ionomycin.