Validation of Candidate Causal Genes for Abdominal Obesity Which Affect Shared Metabolic Pathways and Networks

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 F2 intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.

[1]  R. Zechner,et al.  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* , 2002, The Journal of Biological Chemistry.

[2]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[3]  Mario Falchi,et al.  Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia , 2022 .

[4]  J. Pennings,et al.  Adipose Gene Expression Response of Lean and Obese Mice to Short‐term Dietary Restriction , 2006, Obesity.

[5]  F. Hu,et al.  A Common Genetic Variant Is Associated with Adult and Childhood Obesity , 2006, Science.

[6]  H. Stefánsson,et al.  Genetics of gene expression and its effect on disease , 2008, Nature.

[7]  Stephen W. Edwards,et al.  Microarray Standard Data Set and Figures of Merit for Comparing Data Processing Methods and Experiment Designs , 2003, Bioinform..

[8]  J. Castle,et al.  An integrative genomics approach to infer causal associations between gene expression and disease , 2005, Nature Genetics.

[9]  Subhajyoti De,et al.  Common variants near MC4R are associated with fat mass, weight and risk of obesity , 2008, Nature Genetics.

[10]  J. Goldstein,et al.  Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  B. A. Janowski.  The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Inouye,et al.  Thermosensitive phenotype of transgenic mice overproducing human glutathione peroxidases. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  R. Collins,et al.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease , 2008, Nature Genetics.

[14]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  H. Devaraj,et al.  Expression of the Gas7 gene and Oct4 in embryonic stem cells of mice. , 2005, Stem cells and development.

[16]  Eric E. Schadt,et al.  Moving toward a system genetics view of disease , 2007, Mammalian Genome.

[17]  John D. Storey,et al.  Mapping the Genetic Architecture of Gene Expression in Human Liver , 2008, PLoS biology.

[18]  C. Bult,et al.  Functional annotation of a full-length mouse cDNA collection , 2001, Nature.

[19]  Eric E Schadt,et al.  Cis-acting expression quantitative trait loci in mice. , 2005, Genome research.

[20]  A. Arnold,et al.  Tissue-specific expression and regulation of sexually dimorphic genes in mice. , 2006, Genome research.

[21]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[22]  P. Monk,et al.  Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  J. Noguera,et al.  Malic enzyme 1 genotype is associated with backfat thickness and meat quality traits in pigs. , 2006, Animal genetics.

[24]  S. Horvath,et al.  Variations in DNA elucidate molecular networks that cause disease , 2008, Nature.

[25]  E. Schadt,et al.  Genetic inheritance of gene expression in human cell lines. , 2004, American journal of human genetics.

[26]  S. Kihara,et al.  Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Schadt,et al.  Genomic analysis of metabolic pathway gene expression in mice , 2005, Genome Biology.

[28]  S. Dhanasekaran,et al.  The FASEB Journal express article 10.1096/fj.04-2415fje. Published online November 17, 2004. , 2022 .

[29]  M. Tota,et al.  Deficiency in cytosolic malic enzyme does not increase acetaminophen-induced hepato-toxicity. , 2008, Basic & clinical pharmacology & toxicology.

[30]  K. Clément,et al.  Unraveling the Genetics of Human Obesity , 2006, PLoS genetics.

[31]  Rachel B. Brem,et al.  Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks , 2008, Nature Genetics.

[32]  S. Kasif,et al.  Network-Based Analysis of Affected Biological Processes in Type 2 Diabetes Models , 2007, PLoS genetics.

[33]  H. Hwang,et al.  gas7: A gene expressed preferentially in growth-arrested fibroblasts and terminally differentiated Purkinje neurons affects neurite formation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  J. Flier,et al.  A Transgenic Model of Visceral Obesity and the Metabolic Syndrome , 2001, Science.

[35]  Steve Horvath,et al.  Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling , 2007, European Journal of Human Genetics.

[36]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[37]  O. Mirochnitchenko,et al.  Chemokine expression in transgenic mice overproducing human glutathione peroxidases. , 2002, Methods in enzymology.

[38]  Philippe Froguel,et al.  Common genetic variation near MC4R is associated with waist circumference and insulin resistance , 2008, Nature Genetics.

[39]  Ellen Kampman,et al.  Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity , 2009, Nature Genetics.

[40]  M. J. MacDonald,et al.  Feasibility of a mitochondrial pyruvate malate shuttle in pancreatic islets. Further implication of cytosolic NADPH in insulin secretion. , 1995, The Journal of biological chemistry.

[41]  F. Liu,et al.  Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Beaudet,et al.  X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death. , 1997, Human molecular genetics.

[43]  Hongyue Dai,et al.  Rosetta error model for gene expression analysis , 2006, Bioinform..

[44]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[45]  Christian Gieger,et al.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation , 2009, Nature Genetics.

[46]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Jun Zhu,et al.  Increasing the Power to Detect Causal Associations by Combining Genotypic and Expression Data in Segregating Populations , 2007, PLoS Comput. Biol..

[48]  K. Park,et al.  Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress. , 2008, Molecular endocrinology.

[49]  Hiroaki Kitano,et al.  The PANTHER database of protein families, subfamilies, functions and pathways , 2004, Nucleic Acids Res..