Abstract
Body weight is a polygenic trait with intricate inheritance patterns. Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits. In this study, we conducted an extensive characterization of regulatory variants associated with body weight-related traits in cattle using multi-omics analysis. First, we identified seven candidate genes by integrating selective sweep analysis and multiple genome-wide association study (GWAS) strategies using imputed whole-genome sequencing data from a population of 1577 individuals. Subsequently, we uncovered 3340 eGenes (genes whose expression levels are associated with genetic variants) across 227 muscle samples. Transcriptome-wide association studies (TWASs) further revealed a total of 532 distinct candidate genes associated with body weight-related traits. Colocalization analyses unveiled 44 genes shared between expression quantitative trait loci (eQTLs) and GWAS signals. Moreover, a comprehensive analysis by integrating GWAS, selective sweep, eQTL, TWAS, epigenomic profiling, and molecular validation highlighted a positively selected genomic region on Bos taurus autosome 6 (BTA6). This locus harbors pleiotropic genes (LAP3, MED28, and NCAPG) and a prioritized functional variant involved in the complex regulation of body weight. Additionally, convergent evolution analysis and phenome-wide association studies underscored the conservation of this locus across species. Our study provides a comprehensive understanding of the genetic regulation of body weight through multi-omics analysis in cattle. Our findings contribute to unraveling the genetic mechanisms governing weight-related traits and shed valuable light on the genetic improvement of farm animals.