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Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.

ABSTRACT: We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of alpha-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene.We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.

SUBMITTER: Gargalovic PS

PROVIDER: S-EPMC2846770 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.

Gargalovic Peter S PS Erbilgin Ayça A Kohannim Omid O Pagnon Joanne J Wang Xuping X Castellani Lawrence L LeBoeuf Renee R Peterson Martha L ML Spear Brett T BT Lusis Aldons J AJ

Circulation. Cardiovascular genetics 20091230 1

<h4>Background</h4>We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.<h4>Methods and results</h4>We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fin ...[more]

PMID: 20160197

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Project description:Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637.

Dataset Information

Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.

Publications

Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.

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