Systems genetic analysis in Diversity Outbred mice informs human bone mineral density GWAS and identifies Qsox1 as a novel determinant of bone strength

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 used Diversity Outbred (DO) mice to directly address these limitations by performing the first systems genetics analysis of over 50 complex skeletal phenotypes. We applied a network approach to cortical bone RNA-seq data to discover 46 genes likely to be causal for human BMD GWAS associations, including the novel genes SERTAD4 and GLT8D2. We also performed GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a novel gene influencing cortical bone accrual and bone strength. Our results provide a new perspective on the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics. Here, we sequenced total RNA from 192 Diversity Outbred marrow-depleted left femurs.针对骨质疏松相关性状的全基因组关联研究（Genome-wide Association Studies, GWAS）已累计发现超过1000个关联位点；然而，此类研究的影响力因因果基因鉴定难度较高，且长期严格聚焦于骨密度（Bone Mineral Density, BMD）而受到显著限制。本研究利用多样性远交系（Diversity Outbred, DO）小鼠，率先针对50余种复杂骨骼表型开展系统遗传学分析，以此直接克服上述研究局限。我们通过网络分析方法处理皮质骨RNA测序（RNA-seq）数据，筛选出46个可能与人类骨密度GWAS关联存在因果关系的基因，其中包括新发现的SERTAD4与GLT8D2两个基因。此外，我们还针对多样性远交系小鼠开展了多骨骼性状的GWAS分析，鉴定出Qsox1为全新基因，可调控皮质骨积累与骨骼强度。本研究结果为骨质疏松症遗传学研究提供了全新视角，并凸显了小鼠模型可为人类遗传学研究提供重要参考的价值。本研究对192根取自多样性远交系小鼠的去骨髓左侧股骨开展了总RNA测序。