title: An integrative genomics approach to infer causal associations between gene expression and disease.
abstract: 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.
authors.affiliation: Rosetta Inpharmatics, Seattle, Washington 98109, USA. eric_schadt@merck.com
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: John
authors.initials: J
authors.lastname: Lamb
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Steve
authors.initials: S
authors.lastname: Edwards
authors.forename: Debraj
authors.initials: D
authors.lastname: Guhathakurta
authors.forename: Solveig K
authors.initials: SK
authors.lastname: Sieberts
authors.forename: Stephanie
authors.initials: S
authors.lastname: Monks
authors.forename: Marc
authors.initials: M
authors.lastname: Reitman
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Pek Yee
authors.initials: PY
authors.lastname: Lum
authors.forename: Amy
authors.initials: A
authors.lastname: Leonardson
authors.forename: Rolf
authors.initials: R
authors.lastname: Thieringer
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Liming
authors.initials: L
authors.lastname: Yang
authors.forename: John
authors.initials: J
authors.lastname: Castle
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Zhu
authors.forename: Shera F
authors.initials: SF
authors.lastname: Kash
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Drake
authors.forename: Alan
authors.initials: A
authors.lastname: Sachs
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: 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
chemical_list: 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