Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cell Syst. 2018 Jun 27;6(6):722-733.e6. doi: 10.1016/j.cels.2018.05.016. Epub 2018 Jun 13.
The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species.
个体脂质种类的遗传学及其在疾病中的相关性在很大程度上尚未得到解决。我们对来自 BXD 小鼠群体的 47 个品系的 385 只小鼠的储存、信号转导、膜和线粒体肝脏脂质进行了分析，这些小鼠分别用普通饲料或高脂肪饲料喂养，并将这些数据与互补的多组学数据集进行了整合。我们确定了几种具有特定表型和分子特征的脂质种类和脂质簇，特别是具有健康和脂肪肝特征的心磷脂种类。遗传分析显示，68%的脂质（lQTL）具有数量性状位点。通过多层次组学分析，我们展示了 lQTL 能够揭示可以调节脂质种类水平的候选基因的可靠性。此外，我们还鉴定了与人类 GWAS 中异常脂质代谢相关的基因定位的 lQTL。这项工作为理解脂质种类的遗传调控和生理意义提供了基础和资源。
