Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Research output: Contribution to journalJournal articlepeer-review


  • Carolina Medina-Gomez
  • John P Kemp
  • Niki L Dimou
  • Eskil Kreiner
  • Alessandra Chesi
  • Babette S Zemel
  • Cindy G Boer
  • Tarunveer S Ahluwalia
  • Hans Bisgaard
  • Evangelos Evangelou
  • Denise H M Heppe
  • Lynda F Bonewald
  • Jeffrey P Gorski
  • Mohsen Ghanbari
  • Serkalem Demissie
  • Gustavo Duque
  • Matthew T Maurano
  • Douglas P Kiel
  • Yi-Hsiang Hsu
  • Bram C J van der Eerden
  • Cheryl Ackert-Bicknell
  • Sjur Reppe
  • Kaare M Gautvik
  • Truls Raastad
  • David Karasik
  • Jeroen van de Peppel
  • Vincent W V Jaddoe
  • André G Uitterlinden
  • Jonathan H Tobias
  • Struan F A Grant
  • Pantelis G Bagos
  • David M Evans
  • Fernando Rivadeneira

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.

Original languageEnglish
Article number121
JournalNature Communications
Number of pages11
Publication statusPublished - 2017

    Research areas

  • Body Weight, Bone Density, Carrier Proteins/genetics, Child, Female, Gene Expression, Genetic Pleiotropy, Genome-Wide Association Study/methods, Humans, Male, Meta-Analysis as Topic, Multivariate Analysis, Musculoskeletal Development/genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, Sterol Regulatory Element Binding Protein 1/genetics

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