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

Abstract

1 One in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the 2 location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of 3 obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association 4 study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI 5 (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger 6 in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of 7 individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 8 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, 9 will inform the biology of body fat distribution and its relationship with disease. 10 11 Introduction 12One in four adults worldwide are either overweight or obese (1,2) and are at increased risk of metabolic disease. 13While higher adiposity increases morbidity and mortality (1,3), epidemiological studies indicate that the location 14 and distribution of excess fat within particular depots is more informative than general adiposity for predicting 15 disease risk. Independent of their overall body mass index (BMI), individuals with higher central adiposity have 16 increased risk of cardiometabolic diseases, including type 2 diabetes (T2D) and stroke (4,5); in contrast, individuals 17 with higher gluteal adiposity have lower risk of such outcomes.(5) Previous studies indicate that fat distribution, as 18 assessed by waist-to-hip ratio (WHR), is a trait with a strong heritable component, independent of overall adiposity 19 (measured by BMI), with twin-based heritability estimates ranging between 30-60% (5,6) and narrow-sense 20 heritability estimates have been estimated at ~50% in women and ~20% in men (5). The most recent genome-wide 21 association study in 224,459 samples implicated 49 loci associated with WHR adjusted for BMI (5), and recent 22Mendelian randomisation studies using known WHR-associated genetic variants showed putative causal effects of 23 higher WHR on T2D and coronary artery disease independently of BMI (7). 25 Results 26With the goal of pinpointing genetic variants associated to body shape and fat distribution and motivated by the 27 recent release of genetic data from half a million individuals (8), we performed a meta-analysis of WHR adjusted for 28 BMI (WHRadjBMI). WHRadjBMI is an easily-measured fat distribution phenotype that correlates well with 29 imaging-based fat distribution measures (9). We performed genome-wide association studies (GWAS) of 30 WHRadjBMI in the UK Biobank data set (8), a collection of 484,563 samples with densely-imputed genotype data, 31 using a linear mixed model (10) to account for relatedness and ancestral heterogeneity. We then combined the 32 results with publicly-available GWAS data generated by the GIANT consortium ...

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

“…Publicly available GWAS summary meta‐analysis statistics were obtained for BMI, WHR, intracerebral hemorrhage (ICH), white matter hyperintensity (WMH) volume, and ischemic stroke. Genetic association results for BMI and WHR were derived from the largest currently available meta‐analysis of European ancestry individuals . Briefly, we used summary‐level genotype data of both sexes from the UK Biobank and the Genetic Investigation of Anthropometric Traits (GIANT) consortium, which tested genome‐wide associations for WHR and BMI in 694,649 subjects.…”

“…Genotyping and bioinformatic genetic analysis of each of these GWAS followed standardized procedures that are harmonized and comparable across the studies. Detailed genotype and phenotype assessment procedures have been previously published . Additional demographic and phenotypic information on the included studies is available in the Table.…”

“…Genetic association results for BMI and WHR were derived from the largest currently available meta-analysis of European ancestry individuals. 8 Briefly, we used summary-level genotype data of both sexes from the UK Biobank and the Genetic Investigation of Anthropometric Traits (GIANT) consortium, which tested genome-wide associations for WHR and BMI in 694,649 subjects. Phenotypes were adjusted for sex, age, and recruitment center and underwent center rank inverse normalization.…”

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

“…We evaluated complete GWAS results in the form of summary statistics ( p values and odds ratios) for clinically diagnosed AD dementia [24] and eight CV-associated RFs, including BMI [47], T2D [28], CAD [31], WHR [18], and plasma lipid levels (TC, TG, LDL, and HDL [44]). We obtained publicly available AD GWAS summary statistic data from the International Genomics of Alzheimer’s Disease Project (IGAP Stages 1 and 2; for additional details, see Supplemental Information and [24]; Table 1).…”

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 (Table ). Of these, highly significant replications were marked for rs3812316, near gene MLXIPL ( P = 4.6 × 10 −12 ) and rs1150442 near gene EYA2 ( P = 1.4 × 10 −6 ) in the recent study of Pulit et al…”