Mouse genome-wide association and systems genetics identifies Lhfp as a regulator of bone mass

PLoS Genet. 2019 May 1;15(5):e1008123. doi: 10.1371/journal.pgen.1008123. eCollection 2019 May.


Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P = 3.1 x 10-12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two separate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts. Furthermore, its expression was regulated by a local expression QTL (eQTL), which overlapped the BMD association. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp-/-) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp-/- mice displayed increased osteogenic differentiation. Lhfp-/- mice also had elevated BMD due to increased cortical bone mass. Lastly, we identified SNPs in human LHFP that were associated (P = 1.2 x 10-5) with heel BMD. In conclusion, we used GWAS and systems genetics to identify Lhfp as a regulator of osteoblast activity and bone mass.

Publication types

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

MeSH terms

  • Animals
  • Bone Density
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Cell Differentiation
  • Chromosome Mapping
  • Female
  • Gene Expression
  • Genome*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Knockout
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Osteogenesis / genetics
  • Osteoporosis / genetics*
  • Osteoporosis / metabolism
  • Osteoporosis / pathology
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Tetraspanins / genetics*


  • Lhfp protein, mouse
  • Oncogene Proteins, Fusion
  • Tetraspanins