Hyperketonemia (HYK) is a metabolic disorder that affects early postpartum dairy cows; however, there has been limited success in identifying genomic variants contributing to HYK susceptibility. We conducted a genome-wide association study (GWAS) using HYK phenotypes based on an intensive screening protocol, interrogated genotype interactions with parity group (GWIS), and evaluated the enrichment of annotated metabolic pathways. Holstein cows were enrolled into the experiment after parturition, and blood samples were collected at four timepoints between 5 and 18 days postpartum. Concentration of blood β-hydroxybutyrate (BHB) was quantified cow-side via a handheld BHB meter. Cows were labeled as a HYK case when at least one blood sample had BHB ≥ 1.2 mmol/L, and all other cows were considered non-HYK controls. After quality control procedures, 1,710 cows and 58,699 genotypes were available for further analysis. The GWAS and GWIS were performed using the forward feature select linear mixed model method. There was evidence for an association between ARS-BFGL-NGS-91238 and HYK susceptibility, as well as parity-dependent associations to HYK for BovineHD0600024247 and BovineHD1400023753. Candidate genes annotated to these single nuclear polymorphism associations have been previously associated with obesity, diabetes, insulin resistance, and fatty liver in humans and rodent models. Enrichment analysis revealed focal adhesion and axon guidance as metabolic pathways contributing to HYK etiology, while genetic variation in pathways related to insulin secretion and sensitivity may affect HYK susceptibility in a parity-dependent matter. In conclusion, the present work proposes several novel marker associations and metabolic pathways contributing to genetic risk for HYK susceptibility.

中文翻译：

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大量采样的荷斯坦奶牛的高酮血症GWAS和依赖于平价的SNP协会的血液中β-羟基丁酸酯浓度。

高酮血症（HYK）是一种代谢异常，会影响产后早期的奶牛。然而，在鉴定导致HYK易感性的基因组变体方面的成功有限。我们基于密集的筛选方案，使用HYK表型进行了全基因组关联研究（GWAS），询问了与奇偶校验组（GWIS）的基因型相互作用，并评估了注释的代谢途径的丰富性。分娩后将荷斯坦奶牛纳入实验，并在产后5至18天之间的四个时间点采集血样。通过手持式BHB仪在牛侧对血液中的β-羟基丁酸（BHB）浓度进行定量。当至少一个血液样本的BHB≥1.2 mmol / L时，将母牛标记为HYK病例，将所有其他母牛视为非HYK对照。经过质量控制程序后，1 710头奶牛和58,699个基因型可供进一步分析。GWAS和GWIS使用前向特征选择线性混合模型方法进行。有证据表明ARS-BFGL-NGS-91238和HYK的敏感性以及BovineHD0600024247和BovineHD1400023753与HYK的奇偶性关联。在人类和啮齿动物模型中，注释为这些单核多态性关联的候选基因先前与肥胖，糖尿病，胰岛素抵抗和脂肪肝有关。富集分析显示，粘着斑和轴突指导是导致HYK病因的代谢途径，而与胰岛素分泌和敏感性有关的途径中的遗传变异可能会影响HYK的易感性。总之，目前的工作提出了几种新颖的标志物关联和代谢途径，这些遗传途径对HYK易感性的遗传风险有贡献。