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

Author

Listed:
  • Basel M. Al-Barghouthi

    (University of Virginia
    University of Virginia)

  • Larry D. Mesner

    (University of Virginia
    University of Virginia)

  • Gina M. Calabrese

    (University of Virginia)

  • Daniel Brooks

    (Harvard Medical School)

  • Steven M. Tommasini

    (Yale School of Medicine)

  • Mary L. Bouxsein

    (Harvard Medical School)

  • Mark C. Horowitz

    (Yale School of Medicine)

  • Clifford J. Rosen

    (Maine Medical Center Research Institute)

  • Kevin Nguyen

    (University of Virginia)

  • Samuel Haddox

    (University of Virginia)

  • Emily A. Farber

    (University of Virginia)

  • Suna Onengut-Gumuscu

    (University of Virginia
    University of Virginia)

  • Daniel Pomp

    (University of North Carolina School of Medicine)

  • Charles R. Farber

    (University of Virginia
    University of Virginia
    University of Virginia)

Abstract

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.

Suggested Citation

  • Basel M. Al-Barghouthi & Larry D. Mesner & Gina M. Calabrese & Daniel Brooks & Steven M. Tommasini & Mary L. Bouxsein & Mark C. Horowitz & Clifford J. Rosen & Kevin Nguyen & Samuel Haddox & Emily A. F, 2021. "Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23649-0
    DOI: 10.1038/s41467-021-23649-0
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    Cited by:

    1. Yang Zhao & Jingyuan Ning & Hongqi Teng & Yalan Deng & Marisela Sheldon & Lei Shi & Consuelo Martinez & Jie Zhang & Annie Tian & Yutong Sun & Shinichi Nakagawa & Fan Yao & Hai Wang & Li Ma, 2024. "Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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