# A Systems Genetics Approach to Identify BMD Genes

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $119,807

## Abstract

Osteoporosis is a sex-dependent, metabolic disease characterized by decreased bone mineral density (BMD),
deterioration of bone microstructure, and increased risk of fracture. BMD is a strong predictor of fracture and a
highly heritable quantitative trait. In recent years, genome-wide association studies (GWASs) have identified
dozens of loci influencing variation in BMD; however, few of the underlying genes have been identified. One
reason that gene discovery has been limited is a lack of transcriptomic data on human bone cells and tissues
that can be used to link GWAS variants to alterations in the expression of causal genes. Here, we address this
deficiency by generating population-scale transcriptomic profiles on the three primary cell types involved in
determining BMD levels: osteoblasts, osteoclasts and osteocytes. These data will be generated from bone and
marrow samples collected from individuals undergoing hip replacement surgery. In the same cohort, we will
generate co-relatable tissue-level (microarchitecture, mineralization, and biomechanical properties) and in vitro
cellular phenotypes (osteoblast and osteoclast activities). In Aim 1, RNA-seq data and high-density genotypes
will be used to identify expression quantitative trait loci (eQTL) that colocalize with BMD GWAS loci. In Aim 2,
we will prioritize genes and determine the mechanisms through which they impact BMD through association
with tissue-level and cellular phenotypes and the investigation of co-expression networks. Genes will also be
tested for association with a nearly identical set of phenotypes in a large outbred mouse population. In Aim 3,
we will determine if SPTBN1, a gene identified in preliminary studies, is causal for a BMD GWAS locus on Chr.
2p16.2, and one additional candidate identified via the studies of Aims 1 and 2 will be tested for an effect on
BMD and other bone traits in vivo. Our novel and innovative approach for informing GWAS will identify genes
responsible for GWAS loci and lead to the discovery of putative therapeutic targets for the prevention and
treatment of bone fragility.

## Key facts

- **NIH application ID:** 10582131
- **Project number:** 3R01AR071657-05S1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Charles R Farber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $119,807
- **Award type:** 3
- **Project period:** 2018-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582131

## Citation

> US National Institutes of Health, RePORTER application 10582131, A Systems Genetics Approach to Identify BMD Genes (3R01AR071657-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10582131. Licensed CC0.

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