Korostishevsky Michael, Steves Claire J, Malkin Ida, Spector Timothy, Williams Frances M K, Livshits Gregory
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Eur J Hum Genet. 2016 Feb;24(2):277-83. doi: 10.1038/ejhg.2015.85. Epub 2015 Apr 22.
The contribution of specific molecular-genetic factors to muscle mass variation and sarcopenia remains largely unknown. To identify endogenous molecules and specific genetic factors associated with appendicular lean mass (APLM) in the general population, cross-sectional data from the TwinsUK Adult Twin Registry were used. Non-targeted mass spec-based metabolomic profiling was performed on plasma of 3953 females (mostly dizygotic and monozygotic twins). APLM was measured using dual-energy X-ray absorptiometry (DXA) and genotyping was genome-wide (GWAS). Specific metabolites were used as intermediate phenotypes in the identification of single-nucleotide polymorphisms associated with APLM using GWAS. In all, 162 metabolites were found significantly correlated with APLM, and explained 17.4% of its variation. However, the top three of them (unidentified substance X12063, urate, and mannose) explained 11.1% (P ≤ 9.25 × 10(-26)) so each was subjected to GWAS. Each metabolite showed highly significant (P ≤ 9.28 × 10(-46)) associations with genetic variants in the corresponding genomic regions. Mendelian randomization using these SNPs found no evidence for a direct causal effect of these metabolites on APLM. However, using a new software platform for bivariate analysis we showed that shared genetic factors contribute significantly (P ≤ 4.31 × 10(-43)) to variance in both the metabolites and APLM--independent of the effect of the associated SNPs. There are several metabolites, having a clear pattern of genetic inheritance, which are highly significantly associated with APLM and may provide a cheap and readily accessible biomarker of muscle mass. However, the mechanism by which the genetic factor influences muscle mass remains to be discovered.
特定分子遗传因素对肌肉质量变化和肌肉减少症的贡献在很大程度上仍不清楚。为了确定一般人群中与四肢瘦体重（APLM）相关的内源性分子和特定遗传因素，使用了来自英国双胞胎成人双胞胎登记处的横断面数据。对3953名女性（大多为异卵双胞胎和同卵双胞胎）的血浆进行了基于非靶向质谱的代谢组学分析。使用双能X线吸收法（DXA）测量APLM，并进行全基因组基因分型（GWAS）。在使用GWAS识别与APLM相关的单核苷酸多态性时，将特定代谢物用作中间表型。总共发现162种代谢物与APLM显著相关，并解释了其17.4%的变异。然而，其中排名前三的代谢物（未鉴定物质X12063、尿酸盐和甘露糖）解释了11.1%（P≤9.25×10⁻²⁶），因此对每种代谢物都进行了GWAS。每种代谢物在相应基因组区域与遗传变异均显示出高度显著的关联（P≤9.28×10⁻⁴⁶）。使用这些单核苷酸多态性进行孟德尔随机化分析未发现这些代谢物对APLM有直接因果效应的证据。然而，使用一个新的双变量分析软件平台，我们发现共享遗传因素对代谢物和APLM的变异均有显著贡献（P≤4.31×10⁻⁴³）——独立于相关单核苷酸多态性的影响。有几种代谢物具有明确的遗传继承模式，与APLM高度显著相关，可能提供一种廉价且易于获取的肌肉质量生物标志物。然而，遗传因素影响肌肉质量的机制仍有待发现。
