Mendelian randomization and colocalization reveal potential causal effects of average daily gain on carcass...

Selective breeding has substantially improved productive and reproductive traits in pigs. Yet, these traits are biologically interconnected, and selection for one often affects others in unintended ways. While genome-wide association studies (GWAS) have uncovered many loci linked to these traits, they provide limited insight into causal mechanisms. Mendelian randomization (MR) provides a robust framework for inferring causality and identifying shared genetic determinants. Here, we integrated MR, colocalization, and functional genomics to investigate the biological links between growth, carcass composition, and reproduction in pigs.

Using average daily gain (ADG) as the exposure, MR revealed potentially significant causal effects (P < 0.05) of ADG on carcass composition traits, including backfat thickness (BFT: $\hat{b}_{\mathrm{xy}}^{}$ = 0.13) and loin muscle depth (LMDEP: $\hat{b}_{\mathrm{xy}}^{}$ = 0.35), suggesting a potential causal contribution of increased ADG to both fat deposition and muscle development. Additionally, ADG showed a negative causal association with age at first farrowing (AFF: $\hat{b}_{\mathrm{xy}}^{}$ = -3.24), indicating that faster growth promotes earlier sexual maturity and reproductive onset. In addition to the statistical evidence, gene annotation of instrumental variants (IVs) identified overlapping candidate genes, which may help explain the causal associations observed across the four exposure-outcome analyses. Among these, MC4R and CDH20 were supported by colocalization analysis, indicating shared genetic signals potentially linking growth, carcass composition, and reproductive traits. Integrative analysis supported the tissue-specific roles of these genes in regulating growth, carcass composition, and reproduction.

Our findings suggest a shared genetic architecture and provide potential evidence of a causal influence of ADG on carcass composition and reproductive traits in pigs. This integrative framework supports the development of multi-trait breeding strategies that enhance productivity while managing inherent trade-offs in regulating complex traits.