Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

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.

PMID: 28257690
PMCID: PMC5339333
DOI: 10.1016/j.ajhg.2017.01.027

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Mete Civelek et al. Am J Hum Genet. 2017.

. 2017 Mar 2;100(3):428-443.

doi: 10.1016/j.ajhg.2017.01.027.

Authors

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.

PMID: 28257690
PMCID: PMC5339333
DOI: 10.1016/j.ajhg.2017.01.027

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.

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Figures

**Figure 1**
Example Subcutaneous Adipose eQTL Genes at GWAS Loci (A) The adipose eQTL of *FST* is coincident with the adiponectin GWAS locus *ARL15*. Regional association of variants with expression level of *FST* is shown with the GWAS variant rs6450176 plotted as the index (purple diamond). LD is colored on the basis of the METSIM population. (B) Association between adiponectin level and *FST* expression level in METSIM. (C) The adipose eQTL of *RQCD1* is coincident with the *USP37* GWAS locus for BMI. Regional association of variants with expression level of *RQCD1* is shown with the eSNP rs4674320 (r² = 1.0 with BMI index SNP rs492400) plotted as the index. (D and E) Association between (D) BMI and *RQCD1* expression level in humans from the METSIM study and (E) body fat and *Rqcd1* expression level in mice from the HMDP study.

**Figure 2**
Heatmap of Effect Sizes for Significant Associations between Gene Expression Level and Cardio-Metabolic-Trait Levels at GWAS Loci with Coincident eQTLs Rows show 23 selected cardio-metabolic traits, and columns show the eQTL genes (and reported GWAS trait at the coincident locus). Negative values (blue) indicate that increased gene expression level was associated (p < 0.05) with decreased trait level, whereas positive values (orange) indicate that increased gene expression level was associated with increased trait level.

**Figure 3**
*trans*-eQTL Hotspots in Subcutaenous Adipose Tissue (A) *KLF14 trans*-eQTL hotspot and target genes in subcutaneous adipose tissue. Representation of the location of 55 distal genes for which expression level is associated with rs12154627 at the *KLF14* locus. (B) Representation of the location of 65 distal genes for which expression level is associated with one of four *trans*-eQTL hotspots: *SLC25A38* locus (black), *ZNF800* locus (blue), *CIITA* locus (green), and *HBB* locus (red). Arrowheads point to the *trans*-eQTL loci, and curves indicate the associations with the four sets of target genes.

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Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Affiliations

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Authors

Affiliations

Abstract

Figures

References

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Substances

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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