Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ x SM/J intercross. J Lipid Res 2012 Jun;53(6):1163-75
Date
04/14/2012Pubmed ID
22498810Pubmed Central ID
PMC3351823DOI
10.1194/jlr.M025833Scopus ID
2-s2.0-84861437612 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
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.
Author List
Leduc MS, Blair RH, Verdugo RA, Tsaih SW, Walsh K, Churchill GA, Paigen BAuthor
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Cholesterol, HDL
Chromosomes, Mammalian
Dogs
Female
Genomics
Humans
Hybridization, Genetic
Lipase
Male
Mice
Molecular Sequence Data
Quantitative Trait Loci
Rats
Systems Biology