Greater number and phenotypic relevance of co-occurring gene sets in CHD probands. (A) Counts of gene pairs that were transmitted to offspring more often than expected by chance. Oligogenic pairs were found among probands at a greater rate than their pseudosibling controls for all three variant severity cutoffs, with asterisks indicating significance level: FDR-corrected P-value, (****) P ≤ 1 × 10−10, (***) P ≤ 1 × 10−5, (**) P ≤ 1 × 10−3). (B) Counts of highest-order oligogenic sets transmitted more often than expected by chance to probands and pseudosiblings. Highest-order gene sets were found among probands at a greater rate than their pseudosibling controls, with asterisks indicating significance as in A. (C) GO term enrichment of genes in CHD oligogenic pairs found in probands (left) and pseudosibling controls (right). GO terms are plotted based on fold enrichment and the inverse log of Fisher's exact test P-value. Point color indicates whether a GO term was enriched for known CHD genes or was enriched at or above marginal significance for genes in proband oligogenic pairs (indicated by the dotted line at FDR < 0.1), but not enriched for known CHD genes. Pseudosibling set genes were not enriched for any GO terms at or above marginal significance (FDR = 0.1). (D) Odds that at least two genes in an oligogenic set (pairs and highest-order) occurred in CHD probands and co-occur in a canonical gene set, pathway, or protein–protein interaction. Color indicates the inverse log P-value of the odds ratio (Fisher's exact test). (HPO) Human Phenotype Ontology. (E) Network visualization of oligogenic sets containing two or more differentially expressed genes (circular nodes) identified together in at least one cardiac cell type (octagonal nodes), sourced from six studies. Thin edges indicate differential expression of a gene within the cell type compared with other study cell populations; bold edges between gene nodes indicate genes that were discovered together in a GCOD oligogenic set. (CMs) Cardiomyocytes, (ECs) endothelial cells; (A/V) atrial/ventricular, (AHF) anterior heart field, (OFT) outflow tract, (RV) right ventricle.
