Multi-omics integration reveals Chr1 associated QTL mediating backfat thickness in pigs.

Background: Backfat thickness (BFT) is a vital economic trait in pigs, reflecting subcutaneous fat levels that affect meat quality and production efficiency. As a complex trait shaped by multiple genetic factors, BFT has been studied using genome-wide association studies (GWAS) and linkage analyses to locate fat-related quantitative trait loci (QTLs), but pinpointing causal variants and genes is hindered by linkage disequilibrium and limited regulatory data. This study aimed to dissect the QTLs affecting BFT on Sus scrofa chromosome 1 (SSC1), elucidating regulatory variants, effector genes, and the cell types involved.

Results: Using whole-genome genotyping data from 3,578 pigs and phenotypic data for five BFT traits, we identified a 630.6 kb QTL on SSC1 significantly associated with these traits via GWAS and fine-mapping, pinpointing 34 candidate causal variants. Using deep convolutional neural networks to predict regulatory activity from sequence data integrated with detailed pig epigenetic profiles, we identified five SNPs potentially affecting enhancer activity in specific tissues. Notably, rs342950505 (SSC1:161,123,588) influences weak enhancer activity across multiple tissues, including the brain. High-throughput chromosome conformation capture (Hi-C) analysis identified that rs342950505 interacts with eight genes. Chromatin state annotations confirmed enhancer activity at this QTL in the cerebellum. Leveraging these insights, single-cell ATAC-seq revealed a chromatin accessibility peak encompassing rs342950505 that regulates PMAIP1 expression in inhibitory neurons via enhancer-mediated mechanisms, with an adjacent peak modulating CCBE1 expression in neuroblasts and granule cells. Transcriptome-wide association studies (TWAS) confirmed PMAIP1's role in the hypothalamus, and Mendelian randomization (MR) validated PMAIP1 and CCBE1 as key brain expression quantitative trait locus (eQTL) effectors. We propose that the variant rs342950505, located within a regulatory peak, modulates PMAIP1 expression in inhibitory neurons, potentially influencing energy homeostasis via hypothalamic regulation. Similarly, CCBE1 may contribute to this process.

Conclusions: Our results, through systematic dissection of pleiotropic BFT-associated loci, provide a framework to elucidate regulatory mechanisms of complex traits, offering insights into polygenic control through lipid metabolism and neural signaling pathways.