Genome‐Wide Association Study Identifies Novel Loci Influencing Growth Traits in Pigs

Growth traits in pigs are governed by complex polygenic architectures, with most associated loci residing in non-coding regions that exert substantial influence on economically relevant phenotypes. However, the molecular mechanisms underlying these regulatory elements remain poorly characterized. In this study, a non-coding mutation-designated as NR2C2 recognition motif sequence variation (NRMSV), located 2083 bp upstream of the HMGA1 gene-was identified as a functional modulator of growth traits in a three-generation Eurasian hybrid pig population. NR2C2 is a nuclear receptor implicated in skeletal development and metabolic regulation, while HMGA1 is a key determinant of body size across mammalian species. In embryonic fibroblasts, where NR2C2 is abundantly expressed, the mutant NRMSV suppressed transcriptional activity, functioning as a silencer. In contrast, in bone marrow mesenchymal stem cells, characterized by low NR2C2 expression, the same allele acted as a robust transcriptional enhancer. Knockdown of NR2C2 in embryonic fibroblasts abrogated this repression and restored enhancer activity, confirming the context-dependent, bidirectional regulatory effect of NRMSV on HMGA1 expression. These findings establish the NR2C2-NRMSV-HMGA1 pathway as a novel regulatory mechanism underpinning phenotypic variation in pig growth traits, offering mechanistic insights into mammalian developmental regulation and informing targeted genomic selection for improved productivity in porcine breeding programs.