title: Contribution of Heritability and Epigenetic Factors to Skeletal Muscle Mass Variation in United Kingdom Twins.
abstract: BACKGROUND
  Skeletal muscle mass (SMM) is one of the major components of human body composition, with deviations from normal values often leading to sarcopenia.
  
  
  OBJECTIVE
  Our major aim was to conduct a genome-wide DNA methylation study in an attempt to identify potential genomic regions associated with SMM.
  
  
  METHODS
  This was a mixed cross-sectional and longitudinal study.
  
  
  METHODS
  Community-based study.
  
  
  METHODS
  A total of 1550 middle-aged United Kingdom twins (monozygotic [MZ] and dizygotic [DZ]), 297 of which were repeatedly measured participated in the study.
  
  
  METHODS
  Appendicular lean mass assessed using dual-energy X-ray absorptiometry technology, and methylated DNA immunoprecipitation sequencing DNA methylation profiling genome-wide were obtained from each individual.
  
  
  RESULTS
  Heritability estimate of SMM, with simultaneous adjustment for covariates obtained using variance decomposition analysis, was h(2) = 0.809 ± 0.050. After quality control and analysis of longitudinal stability, the DNA methylation data comprised of 723 029 genomic sites, with positive correlations between repeated measurements (Rrepeated = 0.114-0.905). Correlations between MZ and DZ twins were 0.51 and 0.38 at a genome-wide average, respectively, and clearly increased with Rrepeated. Testing for DNA methylation association with SMM in 50 discordant MZ twins revealed 36 081 nominally significant results, of which the top-ranked 134 signals (P < .01 and Rrepeated > 0.40) were subjected to replication in the sample of 1196 individuals. Seven SMM methylation association signals replicated at a false discovery rate less than 0.1, and these were located in or near genes DNAH12, CAND1, CYP4F29P, and ZFP64, which have previously been highlighted in muscle-related studies. Adjusting for age, smoking, and blood cell heterogeneity did not alter significance of these associations.
  
  
  CONCLUSIONS
  This epigenome-wide study, testing longitudinally stable methylation sites, discovered and replicated a number of associations between DNA methylation at CpG loci and SMM. Four replicated signals were related to genes with potential muscle functions, suggesting that the methylome of whole blood may be informative of SMM variation.
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Gregory
authors.initials: G
authors.lastname: Livshits
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Malkin
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Needhamsen
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Ward
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Department of Twin Research and Genetic Epidemiology (G.L., M.N., W.Y., C.G.B., K.W., J.T.B., T.D.S.), King's College London, London SE1 7EH, United Kingdom; Human Population Biology Research Unit (G.L., I.M.), Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Beijing Genomics Institute-Shenzhen (F.G., Y.X., Y.L., J.W.), Shenzhen 518083, China; King Abdulaziz University (J.W.), Jeddah 22254, Saudi Arabia; and Department of Biology (J.W.) and The Novo Nordisk Foundation Center for Basic Metabolic Research (J.W.), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D015502:Absorptiometry, Photon; D001823:Body Composition / Q000235:genetics*; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D004398:Dyneins / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D008137:Longitudinal Studies; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging*; D012042:Registries; D014157:Transcription Factors / Q000235:genetics; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*; D006113:United Kingdom
chemical_list: C486317:CAND1 protein, human; D004268:DNA-Binding Proteins; C099884:DNAH12 protein, human; D014157:Transcription Factors; C524088:ZFP64 protein, human; D004398:Dyneins