A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis

Abstract Low bone mass and an increased risk of fracture are predictors of osteoporosis. Individuals who share the same bone-mineral density (BMD) vary in their fracture risk, suggesting that microstructural architecture is an important determinant of skeletal strength. Here, we utilized the rich di...

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Autores principales:	Roei Levy, Clemence Levet, Keren Cohen, Matthew Freeman, Richard Mott, Fuad Iraqi, Yankel Gabet
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/01ceaac7d6744b299360855e09d5691f
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spelling	oai:doaj.org-article:01ceaac7d6744b299360855e09d5691f2021-12-02T16:23:10ZA genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis10.1038/s41598-020-60146-82045-2322https://doaj.org/article/01ceaac7d6744b299360855e09d5691f2020-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-60146-8https://doaj.org/toc/2045-2322Abstract Low bone mass and an increased risk of fracture are predictors of osteoporosis. Individuals who share the same bone-mineral density (BMD) vary in their fracture risk, suggesting that microstructural architecture is an important determinant of skeletal strength. Here, we utilized the rich diversity of the Collaborative Cross mice to identify putative causal genes that contribute to the risk of fractures. Using microcomputed tomography, we examined key structural features that pertain to bone quality in the femoral cortical and trabecular compartments of male and female mice. We estimated the broad-sense heritability to be 50–60% for all examined traits, and we identified five quantitative trait loci (QTL) significantly associated with six traits. We refined each QTL by combining information inferred from the ancestry of the mice, ranging from RNA-Seq data and published literature to shortlist candidate genes. We found strong evidence for new candidate genes, particularly Rhbdf2, whose close association with the trabecular bone volume fraction and number was strongly suggested by our analyses. We confirmed our findings with mRNA expression assays of Rhbdf2 in extreme-phenotype mice, and by phenotyping bones of Rhbdf2 knockout mice. Our results indicate that Rhbdf2 plays a decisive role in bone mass accrual and microarchitecture.Roei LevyClemence LevetKeren CohenMatthew FreemanRichard MottFuad IraqiYankel GabetNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Roei Levy Clemence Levet Keren Cohen Matthew Freeman Richard Mott Fuad Iraqi Yankel Gabet A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis
description	Abstract Low bone mass and an increased risk of fracture are predictors of osteoporosis. Individuals who share the same bone-mineral density (BMD) vary in their fracture risk, suggesting that microstructural architecture is an important determinant of skeletal strength. Here, we utilized the rich diversity of the Collaborative Cross mice to identify putative causal genes that contribute to the risk of fractures. Using microcomputed tomography, we examined key structural features that pertain to bone quality in the femoral cortical and trabecular compartments of male and female mice. We estimated the broad-sense heritability to be 50–60% for all examined traits, and we identified five quantitative trait loci (QTL) significantly associated with six traits. We refined each QTL by combining information inferred from the ancestry of the mice, ranging from RNA-Seq data and published literature to shortlist candidate genes. We found strong evidence for new candidate genes, particularly Rhbdf2, whose close association with the trabecular bone volume fraction and number was strongly suggested by our analyses. We confirmed our findings with mRNA expression assays of Rhbdf2 in extreme-phenotype mice, and by phenotyping bones of Rhbdf2 knockout mice. Our results indicate that Rhbdf2 plays a decisive role in bone mass accrual and microarchitecture.
format	article
author	Roei Levy Clemence Levet Keren Cohen Matthew Freeman Richard Mott Fuad Iraqi Yankel Gabet
author_facet	Roei Levy Clemence Levet Keren Cohen Matthew Freeman Richard Mott Fuad Iraqi Yankel Gabet
author_sort	Roei Levy
title	A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis
title_short	A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis
title_full	A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis
title_fullStr	A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis
title_full_unstemmed	A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis
title_sort	genome-wide association study in mice reveals a role for rhbdf2 in skeletal homeostasis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/01ceaac7d6744b299360855e09d5691f
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A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis

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