Systems genetics of metabolic health in the BXD mouse genetic reference population.

Cell systems Pub Date : 2024-06-19 Epub Date: 2024-06-11 DOI:10.1016/j.cels.2024.05.006
Xiaoxu Li, Jean-David Morel, Jonathan Sulc, Alessia De Masi, Amélia Lalou, Giorgia Benegiamo, Johanne Poisson, Yasmine Liu, Giacomo V G Von Alvensleben, Arwen W Gao, Maroun Bou Sleiman, Johan Auwerx
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Abstract

Susceptibility to metabolic syndrome (MetS) is dependent on genetics, environment, and gene-by-environment interactions, rendering the study of underlying mechanisms challenging. The majority of experiments in model organisms do not incorporate genetic variation and lack specific evaluation criteria for MetS. Here, we derived a continuous metric, the metabolic health score (MHS), based on standard clinical parameters and defined its molecular signatures in the liver and circulation. In human UK Biobank, the MHS associated with MetS status and was predictive of future disease incidence, even in individuals without MetS. Using quantitative trait locus analyses in mice, we found two MHS-associated genetic loci and replicated them in unrelated mouse populations. Through a prioritization scheme in mice and human genetic data, we identified TNKS and MCPH1 as candidates mediating differences in the MHS. Our findings provide insights into the molecular mechanisms sustaining metabolic health across species and uncover likely regulators. A record of this paper's transparent peer review process is included in the supplemental information.

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BXD 小鼠遗传参考群体代谢健康的系统遗传学。
代谢综合征(MetS)的易感性取决于遗传、环境以及基因与环境之间的相互作用,因此研究其潜在机制具有挑战性。大多数模式生物实验并不包含遗传变异,也缺乏代谢综合征的具体评估标准。在此,我们根据标准临床参数得出了一种连续性指标--代谢健康评分(MHS),并定义了其在肝脏和血液循环中的分子特征。在人类英国生物库中,MHS 与 MetS 状态相关,并可预测未来疾病的发病率,即使没有 MetS 的个体也是如此。通过对小鼠进行定量性状位点分析,我们发现了两个与 MHS 相关的基因位点,并在无关联的小鼠群体中进行了复制。通过对小鼠和人类基因数据进行优先排序,我们确定 TNKS 和 MCPH1 为介导 MHS 差异的候选基因。我们的研究结果让我们深入了解了维持不同物种代谢健康的分子机制,并发现了可能的调节因子。补充信息中包含了本文透明的同行评审过程记录。
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