Abstract
A higher incidence of coronary artery disease is associated with a lower level of HDL-cholesterol. We searched for genetic loci influencing HDL-cholesterol in F2 mice from a cross between MRL/MpJ and SM/J mice. Quantitative trait loci (QTL) mapping revealed one significant HDL QTL (Apoa2 locus), four suggestive QTL on chromosomes 10, 11, 13, and 18 and four additional QTL on chromosomes 1 proximal, 3, 4, and 7 after adjusting HDL for the strong Apoa2 locus. A novel nonsynonymous polymorphism supports Lipg as the QTL gene for the chromosome 18 QTL, and a difference in Abca1 expression in liver tissue supports it as the QTL gene for the chromosome 4 QTL. Using weighted gene co-expression network analysis, we identified a module that after adjustment for Apoa2, correlated with HDL, was genetically determined by a QTL on chromosome 11, and overlapped with the HDL QTL. A combination of bioinformatics tools and systems genetics helped identify several candidate genes for both the chromosome 11 HDL and module QTL based on differential expression between the parental strains, cis regulation of expression, and causality modeling. We conclude that integrating systems genetics to a more-traditional genetics approach improves the power of complex trait gene identification.
Highlights
A higher incidence of coronary artery disease is associated with a lower level of HDL-cholesterol
When the Quantitative trait loci (QTL) was identified in both males and females (MF) and in one sex only, we only report the location of the peak and 95% CI in the males + females population. c logarithm of the odds (LOD) scores were calculated with sex as an additive covariate in the males + females (MF) analysis except for the QTL on chromosome 13, where sex was added as an interactive covariate
We searched for genes that either carry a nonsynonymous coding polymorphism or differ in expression between the parental strains, and that are cis-regulated, correlate with HDL, and are likely to be causal to the QTL
Summary
A higher incidence of coronary artery disease is associated with a lower level of HDL-cholesterol. A combination of bioinformatics tools and systems genetics helped identify several candidate genes for both the chromosome 11 HDL and module QTL based on differential expression between the parental strains, cis regulation of expression, and causality modeling. A higher incidence of coronary artery disease (CAD) is associated with a lower level of HDL-cholesterol [1, 2], which is determined by multiple environmental and genetic factors. Recent genome-wide association studies (GWAS) have identified known HDL genes such as LIPG and CETP in addition to new genes such as GALNT2 [6]. These known genes, explain only a small proportion of the total variation, indicating that additional genes are yet to be discovered.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
