Fig. 4: Genes mapped from epistatic loci show strong functional co-associations.
From: Epistasis regulates genetic control of cardiac hypertrophy
a, UpSet plot showing the number of lo-siRF-prioritized SNVs (dark blue) and their LD-linked (r2 > 0.6) SNVs (light blue, circle 8 in Fig. 3a) functionally mapped to 20 protein-coding genes via positional, eQTL and/or chromatin interaction (CI) mapping in FUMA33. CCDC141 and IGF1R (highlighted red) are prioritized by all three mapping strategies (details in Supplementary Data 4). b, Heatmap of averaged expression (GTEx, 50% winsorization, log2(TPM + 1)) across different tissues for these functionally mapped genes. c, Co-association network built from an enrichment analysis integrating multiple annotated gene set libraries for GO and pathway terms from Enrichr43. Nodes represent genes (green) functionally linked from lo-siRF-prioritized epistatic and hypostatic loci (Table 1) and top enriched GO and pathway terms. Edge width indicates the co-association strength between enriched terms and genes ranked by two-sided P values from an exhaustive permutation of the co-association score for all possible gene–gene combinations in the network (details in Methods and Supplementary Data 6). d, Comparison between the top 10 TFs enriched from genes prioritized (top) and deprioritized (bottom) by lo-siRF. Prioritized genes are functionally linked to lo-siRF-prioritized SNVs (a), while deprioritized genes are genes linked to SNVs that failed to pass the lo-siRF prioritization thresholds. Enrichment was performed against nine TF-annotated gene set libraries from ChEA344 and Enrichr43, ranked by the number of significantly (P < 0.05, two-sided Fisher’s exact test) overlapped libraries (numbers in the ‘nLibraries’ column) and the mean scaled rank across all libraries containing that TF (colored boxes in the ‘nLibraries’ column). The balloon plot shows the lowest two-sided Fisher’s exact test P values (horizontal axis) and the proportion of overlapped genes (balloon size) between the input gene set and the corresponding TF-annotated gene set. DE, differential expression. e, Heatmap showing the TF co-association strength of gene–gene combinations among lo-siRF-prioritized genes relative to randomly selected gene pairs in the co-association network. Further details in Extended Data Fig. 5 and Supplementary Data 7.
