Abstract
Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI>35 kg/m2) and 540 control subjects (BMI<25 kg/m2), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ∼500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5×10−12). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67×10−9), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS.
Highlights
Obesity is the sixth most important risk factor contributing to the overall burden of disease worldwide [1]
No additional loci with genome-wide significance were identified in the genome-wide association studies (GWAS); the fact that FTO readily reached genome-wide significance in a small data set confirmed the high quality of the phenotypes within the sample collection
The MC4R gene is the second gene found by GWAS to be associated with body mass index (BMI) [6], and, while only marginally associated with obesity in our study, its odds ratio was 1.3
Summary
Obesity is the sixth most important risk factor contributing to the overall burden of disease worldwide [1]. Many studies have shown that body weight and obesity are strongly influenced by genetic factors, with heritability estimates in the range of 65–80% [2,3]. With the development of high-throughput genotyping techniques and the implementation of genome-wide association studies (GWAS), common variations, such as those in FTO [5] and MC4R [6], have been associated with obesity and body mass index (BMI). Recent large-scale meta-analysis of multiple GWAS identified additional genes harboring common SNPs that associate with BMI [7,8,9,10]. Associations of BMI with 28 loci reached genome wide significance, including 10 that were reported previously and 18 that were newly identified. Four additional loci were associated with body fat distribution, all of which had been identified previously. Confirmation of existing BMI loci, and detailed analysis on their association with obesity as a binary trait and with other obesity-related quantitative traits, are important at the current stage to move GWAS signals forward and understand their functional consequences
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