title: 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.
authors.affiliation: Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts, United States of America. foxca@nhlbi.nih.gov
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.forename: Mary
authors.initials: M
authors.lastname: Feitosa
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Nancy
authors.initials: N
authors.lastname: Heard-Costa
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Foster
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Greenawalt
authors.forename: Paula
authors.initials: P
authors.lastname: Griffin
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ding
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.forename: Fran
authors.initials: F
authors.lastname: Tylavsky
authors.forename: Iva
authors.initials: I
authors.lastname: Miljkovic
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Kritchevsky
authors.forename: Lenore
authors.initials: L
authors.lastname: Launer
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.forename: J Jeffrey
authors.initials: JJ
authors.lastname: Carr
authors.forename: Vilmunder
authors.initials: V
authors.lastname: Gudnason
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
mesh_terms: D000328:Adult; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D016207:Cytokines / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D060148:HapMap Project; D006801:Humans; D050152:Intra-Abdominal Fat; D008245:Lysophospholipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012727:Sex Characteristics; D050507:Subcutaneous Fat, Abdominal; D044465:White People
chemical_list: D016207:Cytokines; D011506:Proteins; C546006:THNSL2 protein, human; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D008245:Lysophospholipase; C561408:LYPLAL1 protein, human