For any given level of overall adiposity – as commonly quantified by body mass index (BMI) within clinical practice – individuals vary considerably in fat distribution. We and others have noted that increased visceral fat (VAT) is associated with increased cardiometabolic risk, while gluteofemoral fat (GFAT) may be protective. Familial partial lipodystrophy (FPLD) – often caused by rare variants in the LMNA gene – represents an extreme example of this paradigm, leading to a severe shift to visceral fat with subsequent insulin resistance and adverse metabolic profile. By contrast, the inherited basis of body fat distribution in the broader population is not fully understood. Here, we studied up to 38,965 UK Biobank participants with VAT, abdominal subcutaneous (ASAT), and GFAT volumes precisely quantified using abdominal MRI. Because genetic associations with these raw depot volumes were largely driven by variants known to affect BMI, we next studied six phenotypes of local adiposity: VAT adjusted for BMI (VATadjBMI), ASATadjBMI, GFATadjBMI, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 178 unique loci associated with at least one adiposity trait, including 29 newly-identified loci. Rare variant association studies extend prior evidence of association for PDE3B as an important modulator of fat distribution. Sex-specific analyses of local adiposity traits noted overall higher estimated heritability in females, increased effect sizes for identified loci, and 25 female-specific associations. Individuals in the extreme tails of fat distribution phenotypes were highly enriched for predisposing common variants, as quantified using polygenic scores. Taking GFATadjBMI as an example, individuals with extreme values were 3.8-fold (95%CI 2.8 to 5.2) more likely to have a polygenic score within the top 5% of the distribution. These results – using more precise and BMI-independent measures of local adiposity – confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.

中文翻译：

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内脏、腹部皮下和臀股脂肪库的遗传基础

对于任何给定的整体肥胖水平——在临床实践中通常由体重指数 (BMI) 量化——个体的脂肪分布差异很大。我们和其他人已经注意到，内脏脂肪 (VAT) 增加与心脏代谢风险增加有关，而臀股脂肪 (GFAT) 可能具有保护作用。家族性部分脂肪代谢障碍 (FPLD) – 通常由LMNA 中的罕见变异引起基因——代表了这种范式的一个极端例子，导致严重转变为内脏脂肪，随后出现胰岛素抵抗和不利的代谢特征。相比之下，更广泛人群中体脂分布的遗传基础尚未完全了解。在这里，我们研究了多达 38,965 名英国生物银行参与者，他们的增值税、腹部皮下 (ASAT) 和 GFAT 体积使用腹部 MRI 精确量化。由于与这些原始库体积的遗传关联主要由已知影响 BMI 的变异驱动，我们接下来研究了六种局部肥胖表型：根据 BMI 调整的增值税 (VATadjBMI)、ASATadjBMI、GFATadjBMI、VAT/ASAT、VAT/GFAT 和 ASAT/ GFAT。我们确定了 178 个与至少一种肥胖特征相关的独特基因座，包括 29 个新确定的基因座。PDE3B作为脂肪分布的重要调节剂。对局部肥胖特征的性别特异性分析指出，女性总体上估计的遗传力更高，已识别位点的效应量增加，以及 25 个女性特异性关联。脂肪分布表型极端尾部的个体高度富集易感常见变异，如使用多基因评分量化。以 GFATadjBMI 为例，具有极值的个体在分布的前 5% 内具有多基因评分的可能性高 3.8 倍（95%CI 2.8 至 5.2）。这些结果——使用更精确和 BMI 独立的局部肥胖测量——证实脂肪分布是一种高度遗传的特征，对心脏代谢健康结果具有重要意义。