Fig. 4: Genes mapped from epistatic loci interact in multiple functional co-association networks.

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) that are functionally mapped to each of the 21 protein-coding genes by positional, eQTL, and/or chromatin interaction (CI) mapping using FUMA³⁷. CCDC141 and IGF1R (highlighted in red) are prioritized by all the three types of SNV-to-gene mapping. Details can be found in Extended Data 4. b, Heatmap of averaged expression (from GTEx) per tissue type per gene (50% winsorization, log₂(TPM + 1)) for these functionally mapped genes. c, Co-association network built from an enrichment analysis integrating multiple annotated gene set libraries for gene ontology (GO) and pathway terms from Enrichr⁴⁶. The co-association network connects top enriched GO and pathway terms with genes (green nodes in the network) functionally linked from lo-siRF-prioritized epistatic and hypostatic loci (Fig. 2f). Strengths (indicated by the edge width in the network) of the co-association between enriched terms and genes were measured and ranked by the empirical p-value from an exhaustive permutation of the co-association score for all possible gene-gene combinations in the network (Details in Methods and Extended Data 6). d, A comparison between the top 10 transcription factors (TFs) enriched from genes prioritized (top) and deprioritized (bottom) by lo-siRF. The lo-siRF-prioritized genes are genes functionally linked from lo-siRF-prioritized SNVs (panel a). The lo-siRF-deprioritized genes are genes functionally linked from SNVs that failed to pass the lo-siRF prioritization thresholds. For each of the two gene groups, enrichment results against nine TF-annotated gene set libraries from ChEA3⁴⁷ and Enrichr⁴⁶ were integrated and ranked by the number of significantly (FET p < 0.05) 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 FET p-values for each TF (horizontal axis) and the proportion of overlapped genes (balloon size) between the input gene set and the corresponding TF-annotated gene set. 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. More details are available in Extended Data Fig. 5 and Extended Data 7.