Large-scale in silico mapping of complex quantitative traits in inbred mice.
Understanding the genetic basis of common disease and disease-related quantitative traits will aid in the development of diagnostics and therapeutics. The processs of gene discovery can be sped up by rapid and effective integration of well-defined mouse genome and phenome data resources. We describe here an in silico gene-discovery strategy through genome-wide association (GWA) scans in inbred mice with a wide range of genetic variation. We identified 937 quantitative trait loci (QTLs) from a survey of 173 mouse phenotypes, which include models of human disease (atherosclerosis, cardiovascular disease, cancer and obesity) as well as behavioral, hematological, immunological, metabolic, and neurological traits. 67% of QTLs were refined into genomic regions <0.5 Mb with approximately 40-fold increase in mapping precision as compared with classical linkage analysis. This makes for more efficient identification of the genes that underlie disease. We have identified two QTL genes, Adam12 and Cdh2, as causal genetic variants for atherogenic diet-induced obesity. Our findings demonstrate that GWA analysis in mice has the potential to resolve multiple tightly linked QTLs and achieve single-gene resolution. These high-resolution QTL data can serve as a primary resource for positional cloning and gene identification in the research community.
Liu
Pengyuan
P
Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Vikis
Haris
H
Lu
Yan
Y
Wang
Daolong
D
You
Ming
M
D051722:ADAM Proteins / Q000235:genetics; D000072199:ADAM12 Protein; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D004195:Disease Models, Animal; D056726:Genetic Association Studies / Q000379:methods; D008040:Genetic Linkage; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains / Q000145:classification / Q000235:genetics*; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*
D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; C096115:Adam12 protein, mouse