Gene-Set Analysis of GWAS Data Identifies Candidate Genes Associated to Metabolic Stress and Adaptation in Italian Holstein Cows

The identification of markers and genes associated to metabolic stress and adaptation may assist livestock breeders in further improving productive performance and animal welfare. We searched for genes associated to metabolic stress levels in a GWAS study on 397 Italian Holstein dairy cows genotyped with the new GeneSeek GGP Bovine 150k array. Ceruloplasmin, Gamma-Glutamyl Transferase and Paraoxonase blood levels were used as surrogate traits for the level of cow metabolic stress. We used single-marker regression analysis using a mixed model corrected for the fixed effects of farm, parity, days in milk and BCS to identify regions associated to the three target parameters. Single marker p-values were then combined to derive joint significance values in a gene-set analysis. Genes coding for the target proteins (ceruloplasmin-like, CP; gamma-glutamyltransferase 1 and 5, GGT1 and GGT5; paroxonase1, PON1) were significantly associated to plasma protein concentration. Additional associations were found in other genes, including: angiotensin II receptor1 (AGTR1), glutathione S-transferase theta 1 (GSTT1) and 2 (GSTT2), and phospholipid scramblase1 (PLSCR), involved in inflammatory response and oxidative stress. Validation of these results and candidate causal nucleotide characterization with sequence data will contribute to the identification of informative markers to assist selection and to understand the complex physiology of metabolic stress and adaptation in lactating cows.