title: Genomics and metabolomics of muscular mass in a community-based sample of UK females.
abstract: 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.
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Korostishevsky
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Steves
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ida
authors.initials: I
authors.lastname: Malkin
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Spector
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Frances M K
authors.initials: FM
authors.lastname: Williams
authors.affiliation: 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.
authors.forename: Gregory
authors.initials: G
authors.lastname: Livshits
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006801:Humans; D055432:Metabolomics; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic; D006113:United Kingdom