test; Figure 3b), suggesting indirect consequences of transcriptional regulation. We observed a strong 22.3-fold enrichment (P<1.0×10−308; two-sided Fisher’s exact test) of co-regulated gene pairs and a 1.45-fold enrichment of protein–protein interaction (PPI)26 pairs (P=3.5×10−17; two-sided Fisher’s exact test), including co-regulated subunits of the same protein complex (e.g., products of CPSF1 and CPSF7) and receptor-ligand pairs (e.g., products of CSF3 and CSF3R). We note that cell-type-composition effects likely contribute to the enrichment of co-regulated gene pairs, as there was a depletion of co-regulation among 729 effects nominally replicating in scRNA-seq data (OR=0.5, P=0.015, two-sided Fisher’s exact test). Additionally, Hi-C chromatin contacts28 were also enriched for local–distal gene pairs (OR=1.47; P=2.4×10−153; two-sided Fisher’s exact test), suggesting that some trans-eQTLs could be driven by physical contact (Supplementary Figure 9). Altogether, 29,207 (49%) of the reported trans-eQTLs could be assigned a putative biological mechanism (Figure 3c, Supplementary Data 4). However, the trans-eQTL analysis was limited to trait-associated variants, so the observed enrichments might not generalize to all trans-eQTLs.
