Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women

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.

A 680 kb duplication at the FTO locus in a kindred with obesity and a distinct body fat distribution

“…In a large GWAS consisting of 10 557 European individuals, the FTO locus was strongly associated with subcutaneous fat (P ¼ 5.9 Â 10E-08). 36 Relevant to the present report, in a study of 371 adolescents, the rs9939609 FTO SNP was associated with subcutaneous fat in the neck and frontal chest as measured by lipometry. 37 In summary, we found a 680 kb duplication in a subject with extreme obesity and confirmed its presence in multiple family members who were similarly obese and shared an unusual body fat distribution.…”

Replication Study of 15 Recently Published Loci for Body Fat Distribution in the Japanese Population

“…In this study, we investigated whether the 14 recently reported novel waist-hip ratio-associated SNPs 12) and VFA-associated rs1659258 14) also affect VFA or the ratio of VFA to SFA (V/S ratio) in the Japanese population, which is an important factor in the development of metabolic syndrome.…”

“…(THNSL2) gene was identified to be associated with VFA in women by GWAS for VFA and SFA using CT 14) .…”

<i>ADIPOQ</i> polymorphisms are associated with insulin resistance in Japanese women

“…Visceral fat is evaluated by waist circumference, waist-hip ratio, bioelectrical impedance, or more precisely, measurement of visceral fat area (VFA) using computed tomography (CT) [1,15]. Numerous studies have shown that VFA is influenced by genetic loci [16][17][18][19][20][21]. However, despite the observation that ADIPOQ is a promising candidate gene for visceral fat accumulation [22,23], few studies have reported a link between ADIPOQ polymorphisms and VFA.…”

“…ADIPOQ polymorphisms are associated with insulin resistance in Japanese women Aya Kitamoto 1) , Takuya Kitamoto 1) , Rina So 2) , Tomoaki Matsuo 2) , Yoshio Nakata 2) , Hideyuki Hyogo 3) , Hidenori Ochi 3) , Takahiro Nakamura 4) , Seika Kamohara 5) , Nobuyuki Miyatake 6) , Kazuaki Kotani 7) , Ikuo Mineo 8) , Jun Wada 9) , Yuji Ogawa 10) , Masato Yoneda 10) , Atsushi Nakajima 10) , Tohru Funahashi 11) , Shigeru Miyazaki 12) , Katsuto Tokunaga 13) , Hiroaki Masuzaki 14) , Takato Ueno 15) , Kazuaki Chayama 3) , Kazuyuki Hamaguchi 16) , Kentaro Yamada 17) , Toshiaki Hanafusa 18) , Shinichi Oikawa 19) , Toshiie Sakata 20) , Kiyoji Tanaka 2) , Yuji Matsuzawa 7) and Kikuko Hotta 1)…”