Genetic and nongenetic profiling of milk β-hydroxybutyrate and acetone and their associations with ketosis in Holstein cows.

Ketosis is a metabolic disorder of increasing importance in high-yielding dairy cows, but accurate population-wide binary health trait recording is difficult to implement. Against this background, proper Gaussian indicator traits, which can be routinely measured in milk, are needed. Consequently, we focused on the ketone bodies acetone and β-hydroxybutyrate (BHB), measured via Fourier-transform infrared spectroscopy (FTIR) in milk. In the present study, 62,568 Holstein cows from large-scale German co-operator herds were phenotyped for clinical ketosis (KET) according to a veterinarian diagnosis key. A sub-sample of 16,861 cows additionally had first test-day observations for FTIR acetone and BHB. Associations between FTIR acetone and BHB with KET and with test-day traits were studied phenotypically and quantitative genetically. Furthermore, we estimated SNP marker effects for acetone and BHB (application of genome-wide association studies) based on 40,828 SNP markers from 4,384 genotyped cows, and studied potential candidate genes influencing body fat mobilization. Generalized linear mixed models were applied to infer the influence of binary KET on Gaussian-distributed acetone and BHB (definition of an identity link function), and vice versa, such as the influence of acetone and BHB on KET (definition of a logit link function). Additionally, linear models were applied to study associations between BHB, acetone and test-day traits (milk yield, fat percentage, protein percentage, fat-to-protein ratio and somatic cell score) from the first test-day after calving. An increasing KET incidence was statistically significant associated with increasing FTIR acetone and BHB milk concentrations. Acetone and BHB concentrations were positively associated with fat percentage, fat-to-protein ratio and somatic cell score. Bivariate linear animal models were applied to estimate genetic (co)variance components for KET, acetone, BHB and test-day traits within parities 1 to 3, and considering all parities simultaneously in repeatability models. Pedigree-based heritabilities were quite small (i.e., in the range from 0.01 in parity 3 to 0.07 in parity 1 for acetone, and from 0.03-0.04 for BHB). Heritabilites from repeatability models were 0.05 for acetone, and 0.03 for BHB. Genetic correlations between acetone and BHB were moderate to large within parities and considering all parities simultaneously (0.69-0.98). Genetic correlations between acetone and BHB with KET from different parities ranged from 0.71 to 0.99. Genetic correlations between acetone across parities, and between BHB across parities, ranged from 0.55 to 0.66. Genetic correlations between KET, acetone, and BHB with fat-to-protein ratio and with fat percentage were large and positive, but negative with milk yield. In genome-wide association studies, we identified SNP on BTA 4, 10, 11, and 29 significantly influencing acetone, and on BTA 1 and 16 significantly influencing BHB. The identified potential candidate genes NRXN3, ACOXL, BCL2L11, HIBADH, KCNJ1, and PRG4 are involved in lipid and glucose metabolism pathways.