Fig. 4: Genetic variants that alter expression post-transcriptionally are enriched in splice-altering variants that are predicted to induce NMD.

a, Approach for identifying mechanisms of gene regulation, using data from CCHCR1 locus as illustrative example. Genetic variants that associate with chromatin peak height, RNA expression, splicing and so on (molQTL) are identified. The boxplots grouped by genotype at lead SNP depict innerquartiles of phenotype values with whiskers extending to most extreme value no greater than 1.5× IQR from hinge. Multitrait colocalization (Methods) compares alignment of molQTL signals (scatter plots⁵⁴) to identify molQTLs that probably share causal SNP. b, Effect size (β) of H3K27ac hQTLs at promoter versus eQTL effect sizes estimated in each RNA-seq dataset. Correlation summarized with Spearman’s rho coefficient and two-sided significance test. c, Tally of steady-state eGenes by their colocalizing molQTLs. A total of 831 eGenes colocalize (coloc) with an hQTL (*, H3K27ac, H3K4me1, H3K4me3 or H3K36me3), and 518 ‘post-transcriptional’ (post-txn) eGenes (**) do not colocalize with any hQTL but do colocalize with other molQTL, some of which may be sQTL or apaQTL. d, Example eQTL functioning through AS–NMD from poison exon (red). H3K27ac ChIP-seq and RNA-seq coverage grouped by genotype of lead eQTL SNP. The pink inset region (chr22:46,289,343-46,294,094) shows effect on splicing of poison exon, depicted as sashimi plots with relative usage (intronic PSI) of splice junction arcs. e, QQ plot shows inflation of eQTL signal among groups of SNPs (lead SNPs for p-sQTLs and u-sQTLs within the host gene, H3K27ac QTLs within 100 kb of test gene or random test SNPs). f, Similar to b. Top: effect size of p-sQTLs (only significantly affecting productive splice junctions) versus host gene eQTL β. Bottom: effect size of u-sQTLs (significantly affecting at least one unproductive splice junction) versus effect on host gene expression. g, eQTLs consistent with transcriptional regulation (eQTL/hQTLs, purple) in discovery dataset (LCLs) compared with eQTLs consistent with AS–NMD (eQTL/u-sQTLs, red). Left: each eQTL (SNP:gene pair, rows) assessed for eQTL effects in GTEx tissues (columns). Right: cumulative distribution of number tissues with significant effects. The P value for a two-sided Mann–Whitney test is shown.