title: Identification of genes and networks driving cardiovascular and metabolic phenotypes in a mouse F2 intercross.
abstract: To identify the genes and pathways that underlie cardiovascular and metabolic phenotypes we performed an integrated analysis of a mouse C57BL/6JxA/J F2 (B6AF2) cross by relating genome-wide gene expression data from adipose, kidney, and liver tissues to physiological endpoints measured in the population. We have identified a large number of trait QTLs including loci driving variation in cardiac function on chromosomes 2 and 6 and a hotspot for adiposity, energy metabolism, and glucose traits on chromosome 8. Integration of adipose gene expression data identified a core set of genes that drive the chromosome 8 adiposity QTL. This chromosome 8 trans eQTL signature contains genes associated with mitochondrial function and oxidative phosphorylation and maps to a subnetwork with conserved function in humans that was previously implicated in human obesity. In addition, human eSNPs corresponding to orthologous genes from the signature show enrichment for association to type II diabetes in the DIAGRAM cohort, supporting the idea that the chromosome 8 locus perturbs a molecular network that in humans senses variations in DNA and in turn affects metabolic disease risk. We functionally validate predictions from this approach by demonstrating metabolic phenotypes in knockout mice for three genes from the trans eQTL signature, Akr1b8, Emr1, and Rgs2. In addition we show that the transcriptional signatures for knockout of two of these genes, Akr1b8 and Rgs2, map to the F2 network modules associated with the chromosome 8 trans eQTL signature and that these modules are in turn very significantly correlated with adiposity in the F2 population. Overall this study demonstrates how integrating gene expression data with QTL analysis in a network-based framework can aid in the elucidation of the molecular drivers of disease that can be translated from mice to humans.
authors.affiliation: Rosetta Inpharmatics LLC, A wholly owned subsidiary of Merck & Co, Seattle, Washington, United States of America. derry@sagebase.org
authors.forename: Jonathan M J
authors.initials: JM
authors.lastname: Derry
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Cliona
authors.initials: C
authors.lastname: Molony
authors.forename: Doug
authors.initials: D
authors.lastname: MacNeil
authors.forename: Debraj
authors.initials: D
authors.lastname: Guhathakurta
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Mudgett
authors.forename: Kersten
authors.initials: K
authors.lastname: Small
authors.forename: Lahcen
authors.initials: L
authors.lastname: El Fertak
authors.forename: Alain
authors.initials: A
authors.lastname: Guimond
authors.forename: Mohammed
authors.initials: M
authors.lastname: Selloum
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhao
authors.forename: Marie France
authors.initials: MF
authors.lastname: Champy
authors.forename: Laurent
authors.initials: L
authors.lastname: Monassier
authors.forename: Tom
authors.initials: T
authors.lastname: Vogt
authors.forename: Doris
authors.initials: D
authors.lastname: Cully
authors.forename: Andrew
authors.initials: A
authors.lastname: Kasarskis
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001823:Body Composition; D002318:Cardiovascular Diseases / Q000235:genetics*; D002319:Cardiovascular System; D002784:Cholesterol / Q000378:metabolism; D015331:Cohort Studies; D003433:Crosses, Genetic; D004562:Electrocardiography / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D010641:Phenotype; D040641:Quantitative Trait Loci
chemical_list: D002784:Cholesterol