Fig. 4 |. Cell-state-dependent disease and regulatory effect of eQTLs.

a, b, UMAP plots of the single-cell effect sizes of the RA-linked rs4065275 eQTL for ORMDL3 (a) and the irritable bowel disease (IBD)-associated rs11123923 eQTL for IL18R1 (b). c, Left, UMAP plot of the single-cell effect size of the RA-associated rs3087243 eQTL for CTLA4. Right, single-cell normalized expression of the CTLA4 gene scaled from lowest (dark blue) to highest (yellow). For all single-cell eQTL effect UMAP plots, each cell is coloured by its scaled β_total, centred on β_G with the maximum (red) and minimum (blue) determined by the most extreme β_total. For all box plots, each point represents the average log₂(UMI count + 1) across all cells in the indicated cluster in a donor (n = 259), grouped by genotype. Box plots show median (horizontal bar), 25th and 75th percentiles (lower and upper bounds of the box, respectively) and 1.5 × IQR (or minimum and maximum values if they fall within that range; end of whiskers). β values are the average β_total for all cells in the cluster. d, e, Enrichment of eQTL lead effects (d; n = 461) or independent secondary (conditional) effects (e; n = 53) in promoter or T-cell-specific regulatory regions. The analysis was limited to loci in which at least one variant had PIP ≥ 0.5. The grey bars show the average enrichment across all analysed loci; the red bars are limited to those with significant cell-state interaction (LRT q < 0.05 in multivariate model with 7 CVs); and the blue bars show those without significant cell-state interaction. Bars with P ≥ 0.001 (limit of 1,000 permutations) are labelled with their one-sided P value and with corresponding asterisks. Pairs of interacting and non-interacting bars are labelled with a one-sided permutation P value for the difference (interacting minus non-interacting). The grey dotted line indicates enrichment statistic = 1.