TY - JOUR
T1 - Candidate Regulators of Dyslipidemia in Chromosome 1 Substitution Lines Using Liver Co-Expression Profiling Analysis
AU - Xu, Fuyi
AU - Wang, Maochun
AU - Hu, Shixian
AU - Zhou, Yuxun
AU - Collyer, John
AU - Li, Kai
AU - Xu, Hongyan
AU - Xiao, Junhua
N1 - Publisher Copyright:
© Copyright © 2020 Xu, Wang, Hu, Zhou, Collyer, Li, Xu and Xiao.
PY - 2020/1/9
Y1 - 2020/1/9
N2 - 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.
AB - 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.
KW - Chr 1 substitution lines
KW - candidate gene
KW - gene network
KW - genome wide association studies
KW - plasma lipid
UR - http://www.scopus.com/inward/record.url?scp=85078300803&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078300803&partnerID=8YFLogxK
U2 - 10.3389/fgene.2019.01258
DO - 10.3389/fgene.2019.01258
M3 - Article
AN - SCOPUS:85078300803
SN - 1664-8021
VL - 10
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 1258
ER -