Identification of Candidate Genes Regulating HDL Cholesterol Using a Chromosomal Region Expression Array

Abstract

To identify candidate genes encoding QTLs in baboons, we have developed a novel strategy that integrates comparative mapping, bioinformatics, and expression arrays. A genome-wide scan, performed previously on pedigreed baboons to localize QTLs for phenotypes that are known risk factors for atherosclerosis, revealed a QTL on chromosome 18q that influences high-density lipoprotein cholesterol (HDL-C) phenotypes. After ruling out the only two biologically relevant positional candidate genes in this chromosomal region, we combined information from baboon pedigrees and HDL-C phenotypes with a baboon microsatellite marker map, human microsatellite marker maps, and human genome maps to develop a chromosomal region expression array (CREA). The CREA was screened with heterologous liver cDNA from sib-pairs of contrasting HDL-C phenotypes on two different diets, and genes were prioritized for further study by expression profiles. Analysis of gene expression in this restricted chromosomal region, combined with HDL-C phenotypic information, yielded a list of candidate genes for the QTL regulating HDL-C in baboons. Our data demonstrate the power of this strategy for identifying candidate genes encoding QTLs for multigenic traits. This strategy is applicable to many species that serve as models for human diseases and can even be used with human subjects

Identification of Promoter Variants in Baboon Endothelial Lipase That Regulate High-Density Lipoprotein Cholesterol Levels

“…12 Our previous studies have demonstrated that a substantial proportion of variation in HDL1 in these animals is under the control of a single major gene. 13 Prior linkage analyses 14 have localized a quantitative trait locus (QTL) for HDL1 to chromosome 18, and positional cloning of candidate genes in the QTL interval 15 suggested that endothelial lipase (LIPG) was the candidate gene for the HDL1 QTL. 16 In addition, LIPG liver expression studies in a panel of baboons discordant for HDL1 showed an inverse correlation between LIPG liver expression and HDL1 serum concentrations 16 consistent with LIPG studies in mice [17][18][19][20] and LIPG association studies in humans.…”

Cd14,Gbp1, andPla2g2a: three major candidate genes for experimental IBD identified by combining QTL and microarray analyses

“…Combination of gene expression analysis and QTL mapping has been successfully applied to detect major candidate genes or QTL genes in a variety of models of complex diseases (1,12,24,25). With the approach used in this study, the number of genes that should be examined preferentially for their role as modifier genes for experimental IBD was reduced to eight genes.…”

Pharmacogenomics and animal models of schizophrenia

“…In the mouse models that we have developed to identify QTLs implicated in the PPI and AMPHinduced locomotion schizophrenia endophenotypes, combining information from these QTL mapping studies and from mRNA expression studies of genes mapping to the QTLs of interest may be a powerful strategy to identify the specific genetic variants underlying the QTLs of interest [Cox et al, 2002;Lemon et al, 2002]. More specifically, using bioinformatic tools, it is possible to identify nearly all the genes that map within QTLs of interest.…”