Integration of GWAS, pathway and network analyses reveals novel mechanistic insights into the synthesis of milk proteins in dairy cows

The quantities and proportions of protein fractions have notable effects on the nutritional and technological value of milk. Although much is known about the effects of genetic variants on milk proteins, the complex relationships among the set of genes and pathways regulating the different protein fractions synthesis and secretion into milk in dairy cows are still not completely understood. We conducted genome-wide association studies (GWAS) for milk nitrogen fractions in a cohort of 1,011 Brown Swiss cows, which uncovered 170 significant single nucleotide polymorphism (SNPs), mostly located on BTA6 and BTA11. Gene-set analysis and the network-based Associated Weight Matrix approach revealed that the milk proteins associated genes were involved in several biological functions, particularly ion and cation transmembrane transporter activity and neuronal and hormone signalling, according to the structure and function of casein micelles. Deeper analysis of the transcription factors and their predicted target genes within the network revealed that GFI1B, ZNF407 and NR5A1 might act as master regulators of milk protein synthesis and secretion. The information acquired provides novel insight into the regulatory mechanisms controlling milk protein synthesis and secretion in bovine mammary gland and may be useful in breeding programmes aimed at improving milk nutritional and/or technological properties.