Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits.
Forward genetic approaches to identify genes involved in complex traits such as common human diseases have met with limited success. Fine mapping of linkage regions and validation of positional candidates are time-consuming and not always successful. Here we detail a hybrid procedure to map loci involved in complex traits that leverages the strengths of forward and reverse genetic approaches. By integrating genotypic and expression data in a segregating mouse population, we show how clusters of expression quantitative trait loci linking to regions of the genome accurately reflect the underlying perturbation to the transcriptional network induced by DNA variations in genes that control the complex traits. By matching patterns of gene expression in a segregating population with expression responses induced by single-gene perturbation experiments, we show how genes controlling clusters of expression and clinical quantitative trait loci can be mapped directly. We demonstrate the utility of this approach by identifying 5-lipoxygenase as underlying previously identified quantitative trait loci in an F(2) cross between strains C57BL/6J and DBA/2J and showing that it has pleiotropic effects on body fat, lipid levels and bone density.
Mehrabian
Margarete
M
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1679, USA.
Allayee
Hooman
H
Stockton
Jirina
J
Lum
Pek Yee
PY
Drake
Thomas A
TA
Castellani
Lawrence W
LW
Suh
Michael
M
Armour
Christopher
C
Edwards
Stephen
S
Lamb
John
J
Lusis
Aldons J
AJ
Schadt
Eric E
EE
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D015519:Bone Density / Q000235:genetics*; D003433:Crosses, Genetic; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008954:Models, Biological; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000235:genetics; D040641:Quantitative Trait Loci
D008055:Lipids; D047495:PPAR gamma; D001094:Arachidonate 5-Lipoxygenase