Claw diseases and mastitis represent the most important health issues in dairy cattle with a frequently mentioned connection to milk production. Although many studies have aimed at investigating this connection in more detail by estimating genetic correlations, they do not provide information about causality. An alternative is to carry out Mendelian randomization (MR) studies using genetic variants to investigate the effect of an exposure on an outcome trait mediated by genetic variants. No study has yet investigated the causal association of milk yield (MY) with health traits in dairy cattle. Hence, we performed a MR analysis of MY and seven health traits using imputed whole-genome sequence data from 34,497 German Holstein cows. We applied a method that uses summary statistics and removes horizontal pleiotropic variants (having an effect on both traits), which improves the power and unbiasedness of MR studies. In addition, genetic correlations between MY and each health trait were estimated to compare them with the estimates of causal effects that we expected. All genetic correlations between MY and each health trait were negative, ranging from − 0.303 (mastitis) to − 0.019 (digital dermatitis), which indicates a reduced health status as MY increases. The only non-significant correlation was between MY and digital dermatitis. In addition, each causal association was negative, ranging from − 0.131 (mastitis) to − 0.034 (laminitis), but the number of significant associations was reduced to five nominal and two experiment-wide significant results. The latter were between MY and mastitis and between MY and digital phlegmon. Horizontal pleiotropic variants were identified for mastitis, digital dermatitis and digital phlegmon. They were located within or nearby variants that were previously reported to have a horizontal pleiotropic effect, e.g., on milk production and somatic cell count. Our results confirm the known negative genetic connection between health traits and MY in dairy cattle. In addition, they provide new information about causality, which for example points to the negative energy balance mediating the connection between these traits. This knowledge helps to better understand whether the negative genetic correlation is based on pleiotropy, linkage between causal variants for both trait complexes, or indeed on a causal association.

中文翻译：

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对 34,497 头德国荷斯坦奶牛进行孟德尔随机分析，以推断产奶量与健康特征之间的因果关系


爪病和乳腺炎是奶牛最重要的健康问题，经常被提及与产奶有关。尽管许多研究旨在通过估计遗传相关性来更详细地调查这种联系，但它们没有提供有关因果关系的信息。另一种方法是使用遗传变异进行孟德尔随机化 (MR) 研究，以研究暴露对遗传变异介导的结果性状的影响。尚未有研究调查奶牛产奶量 (MY) 与健康特征之间的因果关系。因此，我们使用 34,497 头德国荷斯坦奶牛的推算全基因组序列数据对 MY 和七种健康特征进行了 MR 分析。我们应用了一种使用汇总统计并消除水平多效性变异（对两个性状都有影响）的方法，这提高了 MR 研究的功效和公正性。此外，还估计了 MY 和每个健康特征之间的遗传相关性，以将它们与我们预期的因果效应估计进行比较。 MY 与每个健康特征之间的所有遗传相关性均为负，范围从 − 0.303（乳腺炎）到 − 0.019（指趾皮炎），这表明随着 MY 的增加，健康状况下降。唯一不显着的相关性是 MY 和指趾皮炎之间。此外，每个因果关联都是负的，范围从−0.131（乳腺炎）到−0.034（蹄叶炎），但显着关联的数量减少到五个名义上的和两个实验范围内的显着结果。后者介于 MY 和乳腺炎之间以及 MY 和数字蜂窝织炎之间。确定了乳腺炎、指趾皮炎和指趾蜂窝织炎的水平多效性变异。 它们位于先前报道的具有水平多效性（例如，产奶量和体细胞计数）的变体内部或附近。我们的结果证实了奶牛健康特征与 MY 之间已知的负遗传联系。此外，它们还提供了有关因果关系的新信息，例如指出调节这些特征之间联系的负能量平衡。这些知识有助于更好地理解负遗传相关性是否基于多效性、两个性状复合体的因果变异之间的联系，或者实际上是基于因果关联。