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

• Published in: International Journal of Obesity Vol. 40; no. 4; pp. 662 - 674
• Main Authors: Sung, Y J, Pérusse, L, Sarzynski, M A, Fornage, M, Sidney, S, Sternfeld, B, Rice, T, Terry, J G, Jacobs, D R, Katzmarzyk, P, Curran, J E, Jeffrey Carr, J, Blangero, J, Ghosh, S, Després, J-P, Rankinen, T, Rao, D C, Bouchard, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2016; Nature Publishing Group
• Subjects: 45; 45/43; 59; 59/57; 631/208; 631/208/205/2138; 692/499; 692/699/2743/393; 692/700/139/2818; Abdomen; Adipose tissue; Adipose tissues; Adult; Analysis; Black or African American - genetics; Body fat; Body Mass Index; Body size; Cardiovascular Diseases - etiology; Cardiovascular Diseases - genetics; Cardiovascular Diseases - physiopathology; Chromosome 10; Chromosome 7; Chromosomes; Epidemiology; Female; Genes; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health Promotion and Disease Prevention; Humans; Inflammation; Internal Medicine; Intra-Abdominal Fat - metabolism; Loci; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Middle Aged; Nucleotides; Obesity; original-article; Phenotype; Polymorphism, Single Nucleotide - genetics; Potassium channels; Public Health; Sex; Sex Characteristics; Sex Factors; Single-nucleotide polymorphism; Subcutaneous Fat, Abdominal - metabolism; Systematic review; United States; White People - genetics; United States
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2015.217

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.