title: Gene set enrichment in eQTL data identifies novel annotations and pathway regulators.
abstract: Genome-wide gene expression profiling has been extensively used to generate biological hypotheses based on differential expression. Recently, many studies have used microarrays to measure gene expression levels across genetic mapping populations. These gene expression phenotypes have been used for genome-wide association analyses, an analysis referred to as expression QTL (eQTL) mapping. Here, eQTL analysis was performed in adipose tissue from 28 inbred strains of mice. We focused our analysis on "trans-eQTL bands", defined as instances in which the expression patterns of many genes were all associated to a common genetic locus. Genes comprising trans-eQTL bands were screened for enrichments in functional gene sets representing known biological pathways, and genes located at associated trans-eQTL band loci were considered candidate transcriptional modulators. We demonstrate that these patterns were enriched for previously characterized relationships between known upstream transcriptional regulators and their downstream target genes. Moreover, we used this strategy to identify both novel regulators and novel members of known pathways. Finally, based on a putative regulatory relationship identified in our analysis, we identified and validated a previously uncharacterized role for cyclin H in the regulation of oxidative phosphorylation. We believe that the specific molecular hypotheses generated in this study will reveal many additional pathway members and regulators, and that the analysis approaches described herein will be broadly applicable to other eQTL data sets.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wu
authors.forename: David L
authors.initials: DL
authors.lastname: Delano
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Su
authors.forename: Jeff
authors.initials: J
authors.lastname: Janes
authors.forename: Phillip
authors.initials: P
authors.lastname: McClurg
authors.forename: Serge
authors.initials: S
authors.lastname: Batalov
authors.forename: Genevieve L
authors.initials: GL
authors.lastname: Welch
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
authors.forename: Akira
authors.initials: A
authors.lastname: Kohsaka
authors.forename: Joseph
authors.initials: J
authors.lastname: Bass
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
mesh_terms: D017667:Adipocytes; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D056748:Cyclin H; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005809:Genes, Regulator; D023281:Genomics / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic
chemical_list: C534752:Ccnh protein, mouse; D056748:Cyclin H; D016213:Cyclins