Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Mete Civelek; Ying Wu; Calvin Pan; Chelsea K Raulerson; Arthur Ko; Aiqing He; Charles Tilford; Niyas K Saleem; Alena Stančáková; Laura J Scott; Christian Fuchsberger; Heather M Stringham; Anne U Jackson; Narisu Narisu; Peter S Chines; Kerrin S Small; Johanna Kuusisto; Brian W Parks; Päivi Pajukanta; Todd Kirchgessner; Francis S Collins; Peter S Gargalovic; Michael Boehnke; Markku Laakso; Karen L Mohlke; Aldons J Lusis

doi:10.1016/j.ajhg.2017.01.027

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Am J Hum Genet. 2017 Mar 2;100(3):428-443. doi: 10.1016/j.ajhg.2017.01.027.

Authors

Mete Civelek¹, Ying Wu², Calvin Pan³, Chelsea K Raulerson², Arthur Ko⁴, Aiqing He⁵, Charles Tilford⁵, Niyas K Saleem⁶, Alena Stančáková⁶, Laura J Scott⁷, Christian Fuchsberger⁷, Heather M Stringham⁷, Anne U Jackson⁷, Narisu Narisu⁸, Peter S Chines⁸, Kerrin S Small⁹, Johanna Kuusisto⁶, Brian W Parks³, Päivi Pajukanta⁴, Todd Kirchgessner⁵, Francis S Collins⁸, Peter S Gargalovic⁵, Michael Boehnke⁷, Markku Laakso⁶, Karen L Mohlke¹⁰, Aldons J Lusis¹¹

Affiliations

¹ 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.
² Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ 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.
⁵ Bristol-Myers Squibb, Pennington, NJ 08534, USA.
⁶ Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
⁷ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Department of Twin Research and Genetic Epidemiology, School of Medicine, King's College London, London SE1 7EH, UK.
¹⁰ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: mohlke@med.unc.edu.
¹¹ 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.

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.

MeSH terms

Aged
Animals
Cardiovascular Diseases / genetics*
Databases, Genetic
Gene Expression Profiling
Gene Expression Regulation*
Genome-Wide Association Study
Genotyping Techniques
Humans
Male
Metabolic Syndrome / genetics*
Mice
Middle Aged
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phenotype
Quantitative Trait Loci*
Reproducibility of Results
Subcutaneous Fat / metabolism*
Trans-Activators / genetics
Trans-Activators / metabolism

Substances

MHC class II transactivator protein
Nuclear Proteins
Trans-Activators

Abstract

MeSH terms

Substances

Grants and funding