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

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. Farber, Suna Onengut-Gumuscu, Daniel Pomp and Charles R. Farber ()
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Basel M. Al-Barghouthi: University of Virginia
Larry D. Mesner: 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
Daniel Pomp: University of North Carolina School of Medicine
Charles R. Farber: University of Virginia

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23649-0

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