# Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra Fish

> **NIH NIH R01** · HEBREW REHABILITATION CENTER FOR AGED · 2021 · $694,650

## Abstract

Project Summary/Abstract
Osteoporosis has become a major and growing worldwide public health burden. Due to fears of side effects,
the use of osteoporosis drugs has fallen by as much as 50%. Thus, there is an unmet need to develop new
drugs for osteoporosis; or to develop personalized therapeutic approaches with the ability to takes into account
individual variability for each patient. Using human genetic studies to identify new druggable targets should
overcome the current treatment crisis in osteoporosis. Although GWAS have been successful in discovering
associated genetic variants with complex traits, more than 88% of GWAS loci are non-coding, which makes the
identification of causal variants and their targeted genes a difficult challenge; thus, limits the use of human
genetics information in drug discovery. To overcome these challenges and get better understanding of GWAS
findings, we proposed to utilize whole genome sequencing in large well-phenotyped populations as well as the
CRISPR/Cas9 gene-editing zebrafish model to identify potential causal variants and targeted genes influencing
skeletal integrity. Our findings may eventually lead to new diagnostics and therapeutics of osteoporosis. We
proposed three specific aims, including: 1) Fine-map previous BMD GWAS loci by existing WGS in 10,000
individuals from the Trans-Omics for Precision Medicine (TOPMed) Program to identify potential causal
sequence variants (functional variants) that are responsible for GWAS signals; 2) Identify novel structural
variation and novel rare sequence variants associated with BMD by performing a whole genome scan using
the same 10,000 WGS samples. We will replicate findings in an additional 5,000 samples selected from the
GENOMOS/GEFOS consortium; 3) Functionally characterize up to 30 genes selected from aims 1 and 2 in
knockout zebrafish by CRISPR/Cas9 gene-editing systems. State-of-the-art technologies for rapid phenotyping
in zebrafish will be applied to a broad range of physiologies (skeletal development, ontogenesis, and
regeneration) and characteristics (bone mass accrual, morphology, and mineral density). Our proposal is
fundamentally important and represents the logical next step in skeletal genetics research. The results will lead
to much needed new drug development to overcome the growing treatment gap in osteoporosis.

## Key facts

- **NIH application ID:** 10241898
- **Project number:** 5R01AR072199-04
- **Recipient organization:** HEBREW REHABILITATION CENTER FOR AGED
- **Principal Investigator:** Yi-Hsiang Hsu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $694,650
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241898

## Citation

> US National Institutes of Health, RePORTER application 10241898, Identifying Osteoporosis Genes by Whole Genome Sequencing and Functional Validation in Zebra Fish (5R01AR072199-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241898. Licensed CC0.

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