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

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $773,856

## Abstract

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.

## Key facts

- **NIH application ID:** 10879366
- **Project number:** 1R01AR082880-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Charles R Farber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $773,856
- **Award type:** 1
- **Project period:** 2024-04-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879366

## Citation

> US National Institutes of Health, RePORTER application 10879366, Large-Scale Genetic Analysis of Bone Strength in Diversity Outbred Mice (1R01AR082880-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10879366. Licensed CC0.

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