Multi-Tissue Omics Analysis Uncovers Translational Regulation Underlying Complex Traits in Pigs

Variations in both transcription and translation of genes play a pivotal role in shaping complex traits and disease phenotypes. However, systematic analyses of genetic variants regulating transcription and translation, as well as their contribution to the genetic architecture of complex traits, remain scarce. Here, by generating a multi-omics dataset consisting of 132 datasets (48 transcriptomic, 48 translational, 30 proteomic, and 6 WGS) across 16 tissues from two breeds, with 3 pigs per breed, we demonstrated widespread translational buffering/amplification across tissues and breeds, with translation efficiency (TE) contributing significantly to phenotypic variation. Through integrative analysis of transcriptional and translational profiles, population genetics, and dual-luciferase reporter assays, we developed a novel framework for prioritizing gene regulatory networks (GRNs) underlying complex traits. Using this framework, we identified 33 functional 5'UTR variants linked to pork production traits, modulating 14 target genes through changes in TE. RNA interference assays confirmed the involvement of AQP4 and MYO18B in myogenic differentiation. In particular, the AQP4 variant (chr6_111421187) likely alters TE by modifying RNA secondary structure, while MYO18B variants (chr14_43476491) affect TE via RNA-binding protein interactions. More broadly, our framework can serve as a paradigm for uncovering the genetic basis of complex traits, extending beyond traditional transcriptional regulation.