A uterine-centric view of reproductive senescence: Genetic insights into late-life performance in laying hens.

This study identifies uterus weight as a heritable (h 2 = 0.45) intermediate phenotype that independently associates with late-life egg production and eggshell quality in aged laying hens. Genome-wide association study (GWAS) reveals a genome-wide significant locus on chromosome 3 and suggestive loci on chromosome 11 for uterus weight, mediation analysis statistically decomposed genetic effects into indirect and direct components, with uterus weight serving as a statistically supported intermediate phenotype, thereby uncovering associations missed by conventional GWAS. Integrative multi-omics: transcriptome-wide association study (TWAS), summary-data-based mendelian randomization (SMR) and weighted gene co-expression network analysis (WGCNA) prioritize 11 candidate genes spanning endocrine signaling, lipid metabolism, ion transport, and tissue remodeling. Collectively, these findings establish uterus weight as a biologically central hub connecting genetic variation to reproductive aging, providing potential molecular markers for enhancing laying persistence in extended production cycles.