Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat

Y J Sung, L Pérusse, M A Sarzynski, M Fornage, S Sidney, B Sternfeld, T Rice, J G Terry, D R Jacobs Jr, P Katzmarzyk, J E Curran, J Jeffrey Carr, J Blangero, S Ghosh, J-P Després, T Rankinen, D C Rao, C Bouchard, Y J Sung, L Pérusse, M A Sarzynski, M Fornage, S Sidney, B Sternfeld, T Rice, J G Terry, D R Jacobs Jr, P Katzmarzyk, J E Curran, J Jeffrey Carr, J Blangero, S Ghosh, J-P Després, T Rankinen, D C Rao, C Bouchard

Abstract

Background: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR).

Subjects and methods: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available.

Results: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 × 10(-6)) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10(-7)), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; P=2.42 × 10(-7)). Our sex-specific analyses identified one genome-wide significant (P<5.0 × 10(-8)) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10(-8) to 1.13 × 10(-8)). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively.

Conclusions: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.

Figures

Figure 1. Regional plots for loci showing…
Figure 1. Regional plots for loci showing the strongest evidence of association
Regional plots for loci showing the strongest evidence of association with VAT (panel A), VAT-BMI (panel B), and SAT in women (panel C) SNPs are plotted by position on chromosome against association (−log10 p-value) and estimated recombination rate (from HapMap-CEU). SNPs surrounding the most significant SNP (purple diamond) are color-coded to reflect their LD with this SNP. Genes and the positions of exons as well as the direction of transcription are shown below the plots. These regional plots were generated using LocusZoom (http://csg.sph.umich.edu/locuszoom/)
Figure 2. Biograph analysis of VAT-BMI associated…
Figure 2. Biograph analysis of VAT-BMI associated genes to ‘obesity’ and ‘inflammation’ phenotypes Biograph analysis of VAT-BMI associated genes to ‘obesity’ and ‘inflammation’ phenotypes
A) Biograph generated connectivity graph between ADCY8 gene and obesity. B) Biograph generated connectivity graph between KCNK9 gene and inflammation. The intermediate linking the genes to the phenotype are indicated in a gray background along with the type of interaction.

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