Abstract
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Highlights
The accumulation of abnormal amounts of intra-abdominal fat is associated with serious adverse metabolic and cardiovascular outcomes, including type 2 diabetes (T2D) and atherosclerotic heart disease [1]
We describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR)
Our analyses have identified two loci (TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR
Summary
The accumulation of abnormal amounts of intra-abdominal fat (central adiposity) is associated with serious adverse metabolic and cardiovascular outcomes, including type 2 diabetes (T2D) and atherosclerotic heart disease [1]. Measures of central and overall adiposity are highly correlated (BMI has r2,0.9 with waist circumference [WC] and ,0.6 with waist-hip ratio [WHR], Table S1). WC and WHR are correlated with more precise measures of intra-abdominal fat measured by MRI in obese women (r2,0.6 and 0.5, respectively) [4]. Several lines of evidence indicate that individual variability in patterns of fat distribution involves local, depot-specific processes, which are independent of the predominantly neuronal mechanisms that control overall energy balance. Anthropometric measures of central adiposity are highly heritable [5] and, after correcting for BMI, heritability estimates remain high (,60% for WC and ,45% for WHR) [6]. Uncommon monogenic syndromes (the partial lipodystrophies) demonstrate that DNA variants can have dramatic effects on the development and/or maintenance of specific regional fat-depots [8]
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