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Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.

Nature genetics | 2009

A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.

Pubmed ID: 19270708 RIS Download

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Associated grants

  • Agency: NHLBI NIH HHS, United States
    Id: HL28481
  • Agency: NHLBI NIH HHS, United States
    Id: P01 HL028481
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK072206-04
  • Agency: NHLBI NIH HHS, United States
    Id: HL30568
  • Agency: NHLBI NIH HHS, United States
    Id: P01 HL030568
  • Agency: NIDDK NIH HHS, United States
    Id: DK072206
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK072206

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PANTHER (tool)

RRID:SCR_004869

System that classifies genes by their functions, using published scientific experimental evidence and evolutionary relationships to predict function even in absence of direct experimental evidence. Orthologs view is curated orthology relationships between genes for human, mouse, rat, fish, worm, and fly.

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Entrez Gene (tool)

RRID:SCR_002473

Database for genomes that have been completely sequenced, have active research community to contribute gene-specific information, or that are scheduled for intense sequence analysis. Includes nomenclature, map location, gene products and their attributes, markers, phenotypes, and links to citations, sequences, variation details, maps, expression, homologs, protein domains and external databases. All entries follow NCBI's format for data collections. Content of Entrez Gene represents result of curation and automated integration of data from NCBI's Reference Sequence project (RefSeq), from collaborating model organism databases, and from many other databases available from NCBI. Records are assigned unique, stable and tracked integers as identifiers. Content is updated as new information becomes available.

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C57BL/6J (tool)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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C3H/HeJ (tool)

RRID:IMSR_JAX:000659

Mus musculus with name C3H/HeJ from IMSR.

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