title: Identification and validation of genes affecting aortic lesions in mice.
abstract: Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.
authors.affiliation: Department of Molecular Profiling, Rosetta Inpharmactics LLC, a wholly owned subsidiary of Merck & Co. Inc., Seattle, Washington, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Larry
authors.initials: L
authors.lastname: Peterson
authors.forename: Rolf
authors.initials: R
authors.lastname: Thieringer
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Deignan
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Susanna
authors.initials: S
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Serguei
authors.initials: S
authors.lastname: Stepaniants
authors.forename: John
authors.initials: J
authors.lastname: Beaulaurier
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Wang
authors.forename: Ray
authors.initials: R
authors.lastname: Rosa
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.forename: Jane Ming-Juan
authors.initials: JM
authors.lastname: Luo
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.forename: Andrew
authors.initials: A
authors.lastname: Plump
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Pek Yee
authors.initials: PY
authors.lastname: Lum
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D001011:Aorta; D050197:Atherosclerosis / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics*; D005796:Genes; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors