Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

Abstract

One in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

Genetic risk score predicts risk for overweight and obesity in Finnish preadolescents

“…Of the 16 suggestive SNPs associated with WHtR, variants in or near LTBP1, PDE1C, GALNT17, DPP6, MAP4K5 and EYA2 were nominally associated with BMI or WHR in adult population 17,18,35,36 ( 37 In the present study we utilized Metabochip, a custom genotyping chip for fine-mapping and replication, which includes altogether 200 000 SNPs from loci that were associated, or were promising for several complex metabolic traits for example, type 2 diabetes, cardiovascular diseases, and their key risk factors: BMI, blood glucose, insulin land lipid concentrations and blood pressure back in 2012. 38 We created BMI-GRSs based on data of Speliotes et al, 17 and 30 of these 32 SNPs were incorporated in Metabochip.…”

Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

“…The index SNPs were expanded to give proxy SNPs in high LD (r 2 ≥ 0.8), and the sets of index and proxy SNPs were combined (index/proxy SNPs; Supplementary Material, Table S4). We separately collected sets of imputed SNPs (p < 6.6 x 10 -9 ) at this locus obtained from summary statistics from one WHRadjBMI meta-analysis of 694,649 individuals (38) and from an eBMD meta-analysis of 426,824 individuals (27) (Supplementary Material, Table S5).…”

“…There are two obesity missense variants in TBX15, namely, rs10494217 (G/T, 0.84/0.16; H156N) in exon 3 and rs61730011 (A/C, 0.96/0.04; M566R) in exon 8 ( Fig. 1B, double arrows) (13,38,40). The meta-analysis by Justice et al (13) involving 476,546 individuals (88% EUR) found a highly significant association of both rs10494217 (p = 2 x 10 -14 ) and rs61730011 (p = 3 x 10 -21 ) with WHRadjBMI, and similar results were obtained for the former SNP in the study of Pullit et al (38) Table S5).…”

“…1B, double arrows) (13,38,40). The meta-analysis by Justice et al (13) involving 476,546 individuals (88% EUR) found a highly significant association of both rs10494217 (p = 2 x 10 -14 ) and rs61730011 (p = 3 x 10 -21 ) with WHRadjBMI, and similar results were obtained for the former SNP in the study of Pullit et al (38) Table S5). Rs61730011 is in a codon for an amino acid in the large C-terminal portion of TBX15, which is of unknown function, and has no human paralogs (as determined by BLASTP, https://blast.ncbi.nlm.nih.gov/).…”

“…The index SNPs were expanded to a set of proxy SNPs (r 2 ≥ 0.8 in a 1-Mb window, EUR population from the 1000 Genome Project Phase 3; (75)) by using PLINK v1.9 (76). In addition, we retrieved summary statistics datasets for WHRadjBMI (38) and eBMD (27), which are the largest publicly available summary statistics for these traits, and extracted imputed significant SNPs (p < 6.6 x 10 -9 ) for TBX15 (chr1:118,717,862-119,916,299) and for TBX18 (chr6:84,921,843-86,171,855). For subdividing the Tier-1 SNPs into thinned LD groups (pairwise r 2 > 0.2), EUR, we used the SNPclip function of the LDlink suite (52).…”