Supplementary Figure 5: Further information regarding target prioritizations and validation for rheumatoid arthritis (RA).

a, Enrichment analysis of Pi top 1% prioritized target genes for RA, in terms of targets of approved drugs in RA, juvenile idiopathic arthritis (JIA) or 28 other immune traits. Fisher’s exact test (one-sided) used. b, Gold standard positives (GSPs) were defined from approved drug targets; genes unlikely to be drug targets (gold standard negatives, GSNs) were defined from the gene druggable space in which GSPs and their direct interaction neighbors had been removed. c, Benchmarking Pi, comparing performance of a naïve method (how often a gene is targeted by drugs), and two other genetics-based methods to separate approved drug targets (GSPs) from GSNs. d, Comparing performance of Pi versus Mendelian disease genetics plus network neighbors (identified via random walk). e, TSEA of Pi prioritized target genes for RA, in terms of disease-specific gene expression signatures in RA (compared to unaffected controls). Normalized enrichment score (NES) indicates likelihood of Pi prioritized target genes to be modulated in disease (over- or under-expressed). Disease-specific gene expression signatures are sourced from CREEDS, with cell types or tissues of origin and the primary data source (GSE accession number) indicated. f, Venn diagram illustrating the enrichment of genes with druggable pockets in RA novel targets (defined as top 1% prioritized but excluding targets of current therapeutics in RA). The significance level (P), odds ratio (OR) and 95% confidence interval (CI) calculated according to Fisher’s exact test (one-sided). g, Identification of drug perturbation gene signatures enriched in RA novel targets. The significance level (FDR) calculated according to Fisher’s exact test (one-sided). Novel RA targets in these enriched signatures shown on the left, with targets ordered according to Pi rating. PBMCs, peripheral blood mononuclear cells; LPS, lipopolysaccharide; CML, chronic myeloid leukemia. h, Novel RA targets identified by Pi that are targets of approved drugs in other disease indications, indicating potential repurposing opportunities.