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.
Highlights
Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD)
We present a resource for the systems genetics of bone strength consisting of information on 55 bone traits from over 600 Diversity Outbred (DO) mice, and RNA-seq data from marrow-depleted cortical bone in 192 DO mice
Human GWASs for BMD have identified over 1000 loci
Summary
Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Efforts to dissect the genetic basis of osteoporosis using genome-wide association studies (GWASs) of bone mineral density (BMD) have been tremendously successful, identifying over 1000 independent associations[3,4,5]. These data have the potential to revolutionize our understanding of bone biology and the discovery of novel therapeutic targets[6,7]; progress to date has been limited. These attributes, coupled with the ability to perform detailed and in-depth characterization of bone traits and generate molecular data on bone, position the DO as a platform to assist in addressing the limitations of human studies described above
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