Home LiteratureArticle Details
PMID: 19270708 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Nature genetics ·Vol. 41 ·No. 4 ·2009-04-00 ·Pages 415-23

Yang X, Deignan JL, Qi H, Zhu J, Qian S, Zhong J, Torosyan G, Majid S, Falkard B, Kleinhanz RR, Karlsson J, Castellani LW, Mumick S, Wang K, Xie T, Coon M, Zhang C, Estrada-Smith D, Farber CR, Wang SS, van Nas A, Ghazalpour A, Zhang B, Macneil DJ, Lamb JR, Dipple KM, Reitman ML, Mehrabian M, Lum PY, Schadt EE, Lusis AJ, Drake TA

Abstract

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.

MeSH Terms
Abdomen/anatomy & histology Adipose Tissue/anatomy & histology Animals Carrier Proteins/genetics Disease Models, Animal Female Gene Expression Profiling Genetic Variation Glutathione Peroxidase/genetics Glycoproteins/genetics Humans Liver/physiology Male Mice Mice, Knockout Mice, Transgenic Muscle, Skeletal/anatomy & histology Nerve Tissue Proteins/genetics Obesity/genetics Phenotype Reproducibility of Results Transcription, Genetic Vesicular Transport Proteins
Chemicals
Carrier Proteins GAS7 protein, human Glycoproteins NPC2 protein, human Nerve Tissue Proteins Vesicular Transport Proteins GPX3 protein, human Glutathione Peroxidase
Authors & Affiliations
32 authors, click to expand affiliations / ORCID
Yang Xia
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Deignan Joshua L
Qi Hongxiu
Zhu Jun
Qian Su
Zhong Judy
Torosyan Gevork
Majid Sana
Falkard Brie
Kleinhanz Robert R
Karlsson Jenny
Castellani Lawrence W
Mumick Sheena
Wang Kai
Xie Tao
Coon Michael
Zhang Chunsheng
Estrada-Smith Daria
Farber Charles R
Wang Susanna S
van Nas Atila
Ghazalpour Anatole
Zhang Bin
Macneil Douglas J
Lamb John R
Dipple Katrina M
Reitman Marc L
Mehrabian Margarete
Lum Pek Y
Schadt Eric E
Lusis Aldons J
Drake Thomas A
References (48)
48 references, click to expand
  1. Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase.
    Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10993-8 PMID: 16009937
  2. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
    Science. 2007 May 11;316(5826):889-94 PMID: 17434869
  3. Common variants near MC4R are associated with fat mass, weight and risk of obesity.
    Nat Genet. 2008 Jun;40(6):768-75 PMID: 18454148
  4. Tissue-specific expression and regulation of sexually dimorphic genes in mice.
    Genome Res. 2006 Aug;16(8):995-1004 PMID: 16825664
  5. Increasing the power to detect causal associations by combining genotypic and expression data in segregating populations.
    PLoS Comput Biol. 2007 Apr 13;3(4):e69 PMID: 17432931
  6. Thermosensitive phenotype of transgenic mice overproducing human glutathione peroxidases.
    Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8120-4 PMID: 7667255
  7. gas7: A gene expressed preferentially in growth-arrested fibroblasts and terminally differentiated Purkinje neurons affects neurite formation.
    Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11423-8 PMID: 9736752
  8. The PANTHER database of protein families, subfamilies, functions and pathways.
    Nucleic Acids Res. 2005 Jan 1;33(Database issue):D284-8 PMID: 15608197
  9. Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress.
    Mol Endocrinol. 2008 Sep;22(9):2176-89 PMID: 18562625
  10. A common genetic variant is associated with adult and childhood obesity.
    Science. 2006 Apr 14;312(5771):279-83 PMID: 16614226
  11. Genetic inheritance of gene expression in human cell lines.
    Am J Hum Genet. 2004 Dec;75(6):1094-105 PMID: 15514893
  12. Chemokine expression in transgenic mice overproducing human glutathione peroxidases.
    Methods Enzymol. 2002;353:460-76 PMID: 12078519
  13. Genetics of gene expression and its effect on disease.
    Nature. 2008 Mar 27;452(7186):423-8 PMID: 18344981
  14. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake.
    J Biol Chem. 2002 Mar 1;277(9):7405-11 PMID: 11751882
  15. Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase.
    Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8852-7 PMID: 15184668
  16. X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death.
    Hum Mol Genet. 1997 Oct;6(11):1803-9 PMID: 9302256
  17. A transgenic model of visceral obesity and the metabolic syndrome.
    Science. 2001 Dec 7;294(5549):2166-70 PMID: 11739957
  18. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.
    Am J Hum Genet. 2008 Jan;82(1):139-49 PMID: 18179892
  19. Variations in DNA elucidate molecular networks that cause disease.
    Nature. 2008 Mar 27;452(7186):429-35 PMID: 18344982
  20. Cis-acting expression quantitative trait loci in mice.
    Genome Res. 2005 May;15(5):681-91 PMID: 15837804
  21. Network-based analysis of affected biological processes in type 2 diabetes models.
    PLoS Genet. 2007 Jun;3(6):e96 PMID: 17571924
  22. Unraveling the genetics of human obesity.
    PLoS Genet. 2006 Dec 29;2(12):e188 PMID: 17196040
  23. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  24. Rosetta error model for gene expression analysis.
    Bioinformatics. 2006 May 1;22(9):1111-21 PMID: 16522673
  25. Microarray standard data set and figures of merit for comparing data processing methods and experiment designs.
    Bioinformatics. 2003 May 22;19(8):956-65 PMID: 12761058
  26. Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks.
    Nat Genet. 2008 Jul;40(7):854-61 PMID: 18552845
  27. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.
    Nat Genet. 2009 Jan;41(1):25-34 PMID: 19079261
  28. Expression of the Gas7 gene and Oct4 in embryonic stem cells of mice.
    Stem Cells Dev. 2005 Dec;14(6):664-70 PMID: 16433621
  29. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
    Science. 2007 Jun 1;316(5829):1331-6 PMID: 17463246
  30. Feasibility of a mitochondrial pyruvate malate shuttle in pancreatic islets. Further implication of cytosolic NADPH in insulin secretion.
    J Biol Chem. 1995 Aug 25;270(34):20051-8 PMID: 7650022
  31. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  32. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12675-80 PMID: 12242342
  33. Adipose gene expression response of lean and obese mice to short-term dietary restriction.
    Obesity (Silver Spring). 2006 Jun;14(6):974-9 PMID: 16861601
  34. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12753-8 PMID: 12242332
  35. Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling.
    Eur J Hum Genet. 2007 Jun;15(6):646-57 PMID: 17406644
  36. Malic enzyme 1 genotype is associated with backfat thickness and meat quality traits in pigs.
    Anim Genet. 2006 Feb;37(1):28-32 PMID: 16441292
  37. Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation.
    FASEB J. 2003 Dec;17(15):2266-8 PMID: 14563692
  38. Statistical significance for genomewide studies.
    Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5 PMID: 12883005
  39. Genetics of gene expression surveyed in maize, mouse and man.
    Nature. 2003 Mar 20;422(6929):297-302 PMID: 12646919
  40. An integrative genomics approach to infer causal associations between gene expression and disease.
    Nat Genet. 2005 Jul;37(7):710-7 PMID: 15965475
  41. Moving toward a system genetics view of disease.
    Mamm Genome. 2007 Jul;18(6-7):389-401 PMID: 17653589
  42. Deficiency in cytosolic malic enzyme does not increase acetaminophen-induced hepato-toxicity.
    Basic Clin Pharmacol Toxicol. 2008 Jul;103(1):36-42 PMID: 18346052
  43. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty.
    FASEB J. 2005 Feb;19(2):243-5 PMID: 15548588
  44. Common genetic variation near MC4R is associated with waist circumference and insulin resistance.
    Nat Genet. 2008 Jun;40(6):716-8 PMID: 18454146
  45. Mapping the genetic architecture of gene expression in human liver.
    PLoS Biol. 2008 May 6;6(5):e107 PMID: 18462017
  46. Genomic analysis of metabolic pathway gene expression in mice.
    Genome Biol. 2005;6(7):R59 PMID: 15998448
  47. Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
    Nat Genet. 2008 Feb;40(2):161-9 PMID: 18193043
  48. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.
    Nat Genet. 2009 Jan;41(1):18-24 PMID: 19079260
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.325
Published
2009-04-00
Epub
2009-00-08
Pages
415-23
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2837947
Subset
IM
Grants
NHLBI NIH HHS · HL28481 · United States
NHLBI NIH HHS · P01 HL028481 · United States
NIDDK NIH HHS · R01 DK072206-04 · United States
NHLBI NIH HHS · HL30568 · United States
NHLBI NIH HHS · P01 HL030568 · United States
NIDDK NIH HHS · DK072206 · United States
NIDDK NIH HHS · R01 DK072206 · United States
Databases
GEO
GSE12000
External Links
PubMed source DOI: 10.1038/ng.325 PMC Full Text View journal details
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