Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA.
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Am J Clin Nutr. 2019 Feb 1;109(2):276-287. doi: 10.1093/ajcn/nqy272.
Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.
To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.
We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).
Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.
In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
瘦体重（LM）在移动性和代谢功能方面起着重要作用。我们之前已经确定了与公斤脂肪质量调整后的 LM 相关的五个位点。这种调整可能会降低识别与瘦体重和脂肪质量都相关的遗传信号的能力。
确定不同脂肪质量调整对 LM 遗传结构的影响，并确定额外的 LM 位点。
我们对来自 20 个欧洲血统队列的 38292 名参与者进行了全身体重 LM（使用双能 X 射线吸收法或生物电阻抗分析测量）的全基因组关联分析，调整了性别、年龄、年龄 2 和身高，并进行了或不进行脂肪质量调整（模型 1 不进行脂肪调整；模型 2 按体重百分比调整脂肪质量；模型 3 按公斤调整脂肪质量）。
在另外的 47227 名来自 29 个队列的个体中，成功复制了 7 个位于不同位置的单核苷酸多态性（SNP），包括一个新的 LM 位点（TNRC6B）。基于模型 1 与模型 3 之间关联的强度，我们将 LM 位点分为在同一方向上对瘦体重和脂肪质量都有影响的“相扑选手”位点（FTO 和 MC4R）和仅对 LM 有影响的“健美运动员”位点（VCAN 和 ADAMTSL3）。使用现有的全基因组关联研究数据库，“相扑选手”位点的 LM 增加等位基因与不良代谢特征相关，而“健美运动员”位点的 LM 增加等位基因与代谢保护相关。
总之，我们确定了一个新的 LM 位点（TNRC6B）。我们的结果表明，瘦体重的遗传增加可能对代谢特征产生有害或保护作用，这取决于它与脂肪质量的关系。
