An integrative genomics approach to infer causal associations between gene expression and disease.
A key goal of biomedical research is to elucidate the complex network of gene interactions underlying complex traits such as common human diseases. Here we detail a multistep procedure for identifying potential key drivers of complex traits that integrates DNA-variation and gene-expression data with other complex trait data in segregating mouse populations. Ordering gene expression traits relative to one another and relative to other complex traits is achieved by systematically testing whether variations in DNA that lead to variations in relative transcript abundances statistically support an independent, causative or reactive function relative to the complex traits under consideration. We show that this approach can predict transcriptional responses to single gene-perturbation experiments using gene-expression data in the context of a segregating mouse population. We also demonstrate the utility of this approach by identifying and experimentally validating the involvement of three new genes in susceptibility to obesity.
Schadt
Eric E
EE
Rosetta Inpharmatics, Seattle, Washington 98109, USA. eric_schadt@merck.com
Lamb
John
J
Yang
Xia
X
Zhu
Jun
J
Edwards
Steve
S
Guhathakurta
Debraj
D
Sieberts
Solveig K
SK
Monks
Stephanie
S
Reitman
Marc
M
Zhang
Chunsheng
C
Lum
Pek Yee
PY
Leonardson
Amy
A
Thieringer
Rolf
R
Metzger
Joseph M
JM
Yang
Liming
L
Castle
John
J
Zhu
Haoyuan
H
Kash
Shera F
SF
Drake
Thomas A
TA
Sachs
Alan
A
Lusis
Aldons J
AJ
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D016678:Genome; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008957:Models, Genetic; D009765:Obesity / Q000235:genetics; D040641:Quantitative Trait Loci; D011951:Receptors, Complement / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053781:Transforming Growth Factor beta2
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D011951:Receptors, Complement; D012097:Repressor Proteins; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; C096823:Zfp90 protein, mouse; C085567:complement C3a receptor; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1