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.
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 ...
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