Fig. 2
From: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
Network-eQTL mapping in rats and humans reveals WWP2 as a positive regulator of the ECM transcriptional program. a Genome-wide mapping of the rat ECM network (n = 219 genes) to the genome (1384 SNPs) identifies a trans-acting regulatory locus on rat chromosome 19q12 (spanning 6.22 Mb). b Genetic mapping of the hECM network in DCM patients (n = 96) to a ~10 Mbp region (475 human SNPs) on human chromosome 16 that is syntenic to the rat locus identified in panel a. c Zoom-in of panel b to the locus on human chromosome 16 with the SNP regulating the hECM network (rs9936589, in red), and the linkage disequilibrium (LD) blocks in the genotyped samples (n = 187). d, e Density plot showing the distribution of the Spearman’s pairwise correlations (ρ) between WWP2 expression levels and each of the genes in the hECM network in DCM (d, red) or rTOF hearts (e in red) and control hearts (in gray). P for significance was calculated by Mann–Whitney U test. f Network graph showing the core set of hECM-network genes with strongest significant correlation (FDR < 0.01) to WWP2 in both DCM and rTOF patients. Full results in Supplementary Data 3e. Nodes represent genes and edges denote protein–protein interaction or co-expression in STRING database (https://string-db.org). Node color is mapped to the average correlation of each gene with WWP2 in patients. Genes that are annotated as “extracellular matrix” (ECM) are highlighted with thicker border. g Boxplot of the hECM-network genes (683 genes) summarized by median expression level of the hECM network in the DCM patients and broken down by genotype at the regulatory SNP rs9936589. h Graphical overview of the three main WWP2 protein isoforms. i Left, boxplot of WWP2-FL, WWP2-N, and WWP2-C gene isoform expression levels broken down by genotype at the regulatory SNP rs9936589 (following Kruskal–Wallis test for each WWP2 isoform, FDR corrects for the 18 isoforms detected in DCM heart). Right, Bayesian eQTL mapping, reported as marginal posterior probability of association (MPPI, y-axis) shows the WWP2-N terminal isoform at the WWP2 regulatory locus (1 Mb region centered around the WWP2 gene). NS not significant (FDR > 0.05)
