# Genomics of bone and body composition traits in children

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $645,621

## Abstract

ABSTRACT
Our objective is to identify genes that regulate development of bone density, quality and strength in childhood.
Childhood is a critical window for lifelong musculoskeletal health. Failure to achieve optimal bone accrual during
childhood results in suboptimal peak bone mass and bone fragility later in life. In excess of 50 million older US
adults have osteoporosis or low bone mass. Osteoporosis has a strong heritable component, yet only 20% of
adult bone mineral density (BMD) variability is explained by genetic variants discovered to date. Pediatric studies
should be highly effective in distilling the genetics of this complex phenotype, given (a) the duration of
environmental influences is shorter, and (b) the genetic determinants of growth, body composition and
maturation also influence bone accrual. Uncovering the genetic architecture of childhood bone accrual is critical
for understanding lifelong skeletal health and identifying targets for preventing and treating bone fragility.
Dual energy x-ray absorptiometry (DXA) measures of areal BMD are widely used in genetic studies. With DXA
software advances, elements of bone quality and structural strength can be extracted, along with body
composition parameters known to influence bone accrual. These deeper DXA-derived phenotypes have great
potential to shed further important, novel insights into genetic determinants of the developing skeleton. We have
genome-wide genotyped the NICHD Bone Mineral Density in Childhood Study (BMDCS) cohort which is unique
for its large size, broad age range, high data quality, diversity and longitudinal design. We will derive new
phenotypes from existing DXA and radiograph images, and apply advanced multidimensional phenotyping and
multivariate GWAS methods to identify new loci. GWAS only reports genomic signals associated with a given
trait and not necessarily the precise location of culprit genes. Therefore, we will use high-resolution `variant to
gene mapping' techniques established in our `Center for Spatial and Functional Genomics' to investigate both
previously reported pediatric novel loci and our anticipated new loci. Our approach first prioritizes putative causal
SNPs using open chromatin and enhancer epigenetic signatures, and then identifies 3D genomic contacts
between these prioritized SNPs and their target gene promoters, using a high-resolution promoter-based
chromatin conformation capture technique. To validate these target genes, we will use CRISPR/Cas9 to edit the
putative regulatory SNPs and use siRNA to target genes and show an effect on bone-relevant phenotypes. We
will apply our techniques in primary pediatric human mesenchymal progenitor cell (MSC)-derived osteoblasts, a
very relevant bone cellular model for understanding pediatric bone mass accrual.
Thus, our proposal is an unparalleled opportunity to interrogate novel phenotypes and functionally characterize
the actual effector genes using high resolution chromatin conformation capture...

## Key facts

- **NIH application ID:** 10889956
- **Project number:** 5R01HD100406-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Struan F A Grant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $645,621
- **Award type:** 5
- **Project period:** 2020-08-07 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889956

## Citation

> US National Institutes of Health, RePORTER application 10889956, Genomics of bone and body composition traits in children (5R01HD100406-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10889956. Licensed CC0.

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