Xu Fuyi, Wang Maochun, Hu Shixian, Zhou Yuxun, Collyer John, Li Kai, Xu Hongyan, Xiao Junhua
College of Chemistry, Chemical Engineering, and Biotechnology, Donghua University, Shanghai, China.
Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States.
Front Genet. 2020 Jan 9;10:1258. doi: 10.3389/fgene.2019.01258. eCollection 2019.
Dyslipidemia is a major risk factor for cardiovascular disease. Although many genetic factors have been unveiled, a large fraction of the phenotypic variance still needs further investigation. Chromosome 1 (Chr 1) harbors multiple gene loci that regulate blood lipid levels, and identifying functional genes in these loci has proved challenging. We constructed a mouse population, Chr 1 substitution lines (C1SLs), where only Chr 1 differs from the recipient strain C57BL/6J (B6), while the remaining chromosomes are unchanged. Therefore, any phenotypic variance between C1SLs and B6 can be attributed to the differences in Chr 1. In this study, we assayed plasma lipid and glucose levels in 13 C1SLs and their recipient strain B6. Through weighted gene co-expression network analysis of liver transcriptome and "guilty-by-association" study, eight associated modules of plasma lipid and glucose were identified. Further joint analysis of human genome wide association studies revealed 48 candidate genes. In addition, 38 genes located on Chr 1 were also uncovered, and 13 of which have been functionally validated in mouse models. These results suggest that C1SLs are ideal mouse models to identify functional genes on Chr 1 associated with complex traits, like dyslipidemia, by using gene co-expression network analysis.
血脂异常是心血管疾病的主要危险因素。尽管许多遗传因素已被揭示，但表型变异的很大一部分仍需进一步研究。1号染色体（Chr 1）包含多个调节血脂水平的基因座，而在这些基因座中鉴定功能基因已被证明具有挑战性。我们构建了一个小鼠群体，即1号染色体代换系（C1SLs），其中只有1号染色体与受体品系C57BL/6J（B6）不同，而其余染色体保持不变。因此，C1SLs和B6之间的任何表型变异都可归因于1号染色体的差异。在本研究中，我们测定了13个C1SLs及其受体品系B6的血浆脂质和葡萄糖水平。通过对肝脏转录组进行加权基因共表达网络分析和“关联有罪”研究，确定了八个与血浆脂质和葡萄糖相关的模块。对人类全基因组关联研究的进一步联合分析揭示了48个候选基因。此外，还发现了位于1号染色体上的38个基因，其中13个已在小鼠模型中得到功能验证。这些结果表明，C1SLs是通过基因共表达网络分析来鉴定与复杂性状（如血脂异常）相关的1号染色体上功能基因的理想小鼠模型。
