Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength

Nat Commun. 2021 Jun 7;12(1):3408. doi: 10.1038/s41467-021-23649-0.


Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Density / genetics*
  • Cell Differentiation / genetics
  • Collaborative Cross Mice
  • Datasets as Topic
  • Female
  • Femur / physiology
  • Fluoresceins / administration & dosage
  • Fluorescent Dyes / administration & dosage
  • Genome-Wide Association Study
  • Glycosyltransferases / genetics
  • Humans
  • Male
  • Mesenchymal Stem Cells
  • Mice
  • Mice, Knockout
  • Osteoblasts
  • Osteogenesis / genetics
  • Osteoporosis / genetics*
  • Oxidoreductases Acting on Sulfur Group Donors / genetics*
  • RNA-Seq
  • Single-Cell Analysis


  • Fluoresceins
  • Fluorescent Dyes
  • Oxidoreductases Acting on Sulfur Group Donors
  • QSOX1 protein, mouse
  • Glycosyltransferases
  • fluorexon