Multi-omics integration of Fst, GWAS, TWAS and transcriptomics revealed candidate genes and pathways associated with pneumonia lesion scores in pigs

Respiratory diseases significantly impair pig growth performance by reducing average daily gain and feed conversion efficiency. Pneumonia lesion score (PLS) is a reliable phenotypic indicator for detecting respiratory issues in pig herds, including subclinical infections that often remain undiagnosed. In this study, PLS data was collected from 327 Large White pigs, and whole-genome resequencing (WGS) was performed. Lung tissue samples from pigs with extremely high and low PLS values were subjected to transcriptomic sequencing and Fixation Index (F st ) analysis. Additionally, a transcriptome-wide association study (TWAS) was conducted using FarmGTEx prediction models based on blood and lung tissues. By integrating F st , Genome-Wide Association Study (GWAS), TWAS, and transcriptomic data, we identified key genomic regions and pathways associated with PLS variation, including immune regulation, inflammation, and metabolic adaptation. Candidate genes, RAB11FIP2 and SLC18A2 are implicated in immune modulation: RAB11FIP2 enhances TLR4 signaling and phagocytosis, whereas reduced SLC18A2 expression may compromise monoamine-mediated immune regulation. FBXL13 and ALPK2 , identified via F st and transcriptomic analysis, are linked to macrophage migration and Wnt/β-catenin signaling. Similarly, Genes like TRAF3IP1 and ASB1 , highlighted by F st and GWAS, contribute to ciliary transport, epithelial defense, and regulation of NF-κB and MAPK signaling. Moreover, GWAS and TWAS pinpointed RAMP1 , as a novel candidate gene influencing immune modulation and airway responses through CGRP signaling, vascular tone regulation, and neuro-immune interactions, these findings have not been previously reported in PLS studies. Overall, this study provides novel insights into the genetic mechanisms underlying porcine lung lesions and offers a foundation for breeding strategies aimed at improving respiratory disease resistance and herd health.