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Interactions among genomic loci have often been overlooked in genome-wide association studies, revealing the combinatorial effects of variants on phenotype or disease manifestation. Unexplained genetic variance, interactions among causal genes of small effects, and biological pathways could be identified using a network biology approach. The main objective of this study was to determine the genome-wide epistatic variants affecting feed efficiency traits [feed conversion ratio (FCR) and residual feed intake (RFI)] based on weighted interaction SNP hub (WISH-R) method. Herein, we detected highly interconnected epistatic SNP modules, pathways, and potential biomarkers for the FCR and RFI in Duroc and Landrace purebreds considering the whole population, and separately for low and high feed efficient groups. Highly interacting SNP modules in Duroc (1,247 SNPs) and Landrace (1,215 SNPs) across the population and for low feed efficient (Duroc—80 SNPs, Landrace—146 SNPs) and high feed efficient group (Duroc—198 SNPs, Landrace—232 SNPs) for FCR and RFI were identified. Gene and pathway analyses identified  ABL1 ,  MAP3K4 ,  MAP3K5 ,  SEMA6A ,  KITLG , and  KAT2B  from chromosomes 1, 2, 5, and 13 underlying ErbB, Ras, Rap1, thyroid hormone, axon guidance pathways in Duroc.  GABBR2 ,  GNA12,  and  PRKCG  genes from chromosomes 1, 3, and 6 pointed towards thyroid hormone, cGMP-PKG and cAMP pathways in Landrace. From Duroc low feed efficient group, the  TPK1  gene was found involved with thiamine metabolism, whereas  PARD6G ,  DLG2, CRB1  were involved with the hippo signaling pathway in high feed efficient group.  PLOD1  and  SETD7  genes were involved with lysine degradation in low feed efficient group in Landrace, while high feed efficient group pointed to genes underpinning valine, leucine, isoleucine degradation, and fatty acid elongation. Some SNPs and genes identified are known for their association with feed efficiency, others are novel and potentially provide new avenues for further research. Further validation of epistatic SNPs and genes identified here in a larger cohort would help to establish a framework for modelling epistatic variance in future methods of genomic prediction, increasing the accuracy of estimated genetic merit for FE and helping the pig breeding industry.

Genome-Wide Epistatic Interaction Networks Affecting Feed Efficiency in Duroc and Landrace Pigs