title: Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits.
abstract: Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10-8) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Chelsea K
authors.initials: CK
authors.lastname: Raulerson
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Ko
authors.affiliation: Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.affiliation: Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Tilford
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
authors.forename: Niyas K
authors.initials: NK
authors.lastname: Saleem
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stringham
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.affiliation: Department of Twin Research and Genetic Epidemiology, School of Medicine, King's College London, London SE1 7EH, UK.
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.affiliation: Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gargalovic
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: mohlke@med.unc.edu.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jlusis@mednet.ucla.edu.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000368:Aged; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics*; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D050151:Subcutaneous Fat / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators