Abstract

Metabolites are important intermediate molecular phenotypes that reflect physiological and biochemical processes within an organism. However, the molecular mechanisms linking genetic variation to metabolite abundance remain poorly understood in dairy cattle. Here, we integrated whole-genome sequencing, whole-blood transcriptomic, and plasma metabolomic data from 80 Jersey cattle to investigate the genetic regulation of circulating metabolites. After quality control, 10,696,212 high-quality SNPs, 15,559 expressed genes, and 841 stable plasma metabolites were retained for downstream analyses. Cis-eQTL mapping identified 1863 eGenes regulated by 1,340,105 significant cis-eQTLs. Transcriptome–metabolome association analysis further detected 258 significant gene–metabolite associations involving 148 genes and 177 metabolites. By integrating cis-eQTLs with gene–metabolite associations, mediation analysis identified 218 significant SNP–gene–metabolite trios involving 124 genes and 157 metabolites. Network analysis further identified several highly connected mediator genes, including MEGF9, S1PR5, and CD27 and revealed two distinct mediation patterns, complete and partial mediation. Together, these findings indicate that gene expression serves as an important intermediate layer connecting genetic variation with circulating metabolites. This study provides a comprehensive multi-omics resource for investigating the genetic regulation of the blood metabolome in Jersey cattle and offers new insights into the molecular basis of metabolic variation.

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