May 10, 2012Open Access
Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women
Key Result
Genome-wide association meta-analysis identified a novel locus for visceral adipose tissue in women at rs1659258 near THNSL2 (p = 1.6x10^-08) and a locus for the VAT/SAT ratio at rs11118316 near LYPLAL1 (p = 3.1x10^-09).
Study Design
Type
Meta-Analysis (n=10,557)
Multicenter
Yes
Structured PICO
Does genome-wide association identify novel genetic loci for CT-measured abdominal fat distribution in men and women?
P
Population
10,557 men and women of European ancestry from 4 population-based cohorts underwent computed tomography to quantify abdominal adipose depots for a genome-wide association meta-analysis.
E
Exposure
Genome-wide association analysis using standard arrays imputed to ~2.5 million Hapmap SNPs.
O
Outcome
Subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio quantified using computed tomography (CT).surrogate
Genome-wide association analysis of CT-quantified abdominal fat depots identified a novel locus (rs1659258 near THNSL2) for visceral adipose tissue specifically in women, highlighting the importance of sex-specific analyses in body fat distribution.
Main Result
p-value: p=1.6x10^-08
Limitations
- Modest discovery sample size compared with other contemporary analyses
- Mean BMI in the gastric bypass eQTL dataset was substantially higher than in the discovery GWAS, potentially affecting generalizability
Abstract
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 women, p = 0.49 men). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.