Integrative analysis of quantitative trait loci of alternative polyadenylation and <scp>GWAS</scp> highlights key regulators of milk production and immune traits in Holstein

Understanding the genetic regulation of complex traits like mastitis in Holstein dairy cows remains a challenge, despite significant advancements in breeding techniques. This study integrates 3'-untranslated region alternative polyadenylation (APA) quantitative trait loci (3'aQTL) mapping with genome-wide association studies (GWASs) to identify key genetic variants and regulatory genes influencing traits during early lactation. Heritability analysis showed that, on average, cis-acting SNPs explained 22% of percentage of distal polyA site usage index (PDUI) variance, supporting a genetic basis for APA regulation. Building on this, we identified 1143 significant cis-3'aQTL associated with PDUI variation across 215 genes (3'aGenes), with significant enrichment in immune system and disease-related pathways. Comparisons with expression quantitative trait loci (eQTL) revealed limited overlap, suggesting distinct regulatory mechanisms. SNP rs109421300 was found to co-localize with GWAS signals for milk protein, mastitis and ketosis traits. Further analysis linked rs109421300 to the regulation of GRINA via APA, with predicted transcription factor interactions involving NRF1 and RUNX. These findings enhance our understanding of the genetic basis of economically important traits in dairy cows and provide a foundation for precision breeding strategies.