Large-Scale Genetic Analysis of Bone Strength in Diversity Outbred Mice

Project Summary: Reduced bone strength is a hallmark of many bone disorders, including osteoporosis, a debilitating disease affecting millions of Americans. The strength of bone is influenced by multiple characteristics of bone including microarchitecture, biomechanical properties (e.g., stiffness), and bone mineral density (BMD). Genome-wide association studies (GWASs) have successfully identified over 1100 independent associations for BMD. However, BMD is the only bone strength trait investigated using large-scale GWASs. This is largely due to the inability to directly measure bone strength in vivo and quantify other strength-related traits in humans at scale. The sole focus on BMD has limited the development of a comprehensive understanding of the genetics of bone strength. Here, we propose to use Diversity Outbred (DO) mice to address this limitation. We will perform GWAS in ~5792 mice (an ~9-fold increase in our current sample size) to significantly increase our power for association detection. The following three specific aims will identify novel genes influencing bone strength. In Aim 1, we will perform GWAS for bone strength and multiple strength-related traits in 5792 DO mice and utilize an extensive set of transcriptomics data on bone to identify causal genes. In Aim 2, we will use DO bone strength mapping data to inform human bone mineral density GWAS. In Aim 3, we will validate the role of multiple candidate genes using in vitro and in vivo approaches. We will begin by investigating the role of eyes absent homolog 4 (Eya4) in the regulation of bone strength. In this project we will significantly expand a proven resource to discover new genes impacting bone strength – the most clinically relevant feature of bone, but one that cannot be studied directly in humans. Our approach will significantly expand gene discovery efforts and has the potential to identify dozens of new bone strength loci. These efforts will not only increase our understanding of the biological mechanisms underlying bone strength, but point to new therapeutic targets for the prevention and treatment of low bone strength and skeletal fragility.