# Project 1: Genome Wide Sequencing for Osteoporosis Risk Genes in Males

> **NIH NIH U19** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $724,943

## Abstract

PROJECT SUMMARY
 BMD (bone mineral density) is the most commonly studied major risk factor for osteoporosis (OP). So far, GWAS
studies have identified ~100 BMD marker loci with common variants, in samples with females only or with both
males and females. The identified loci, in total, explain <10% BMD heritability and their sex-specific genetic effects
are largely unknown. In addition, specific functional DNA sequence variants are also generally unknown.
 The Goal of this project is to most comprehensively identify potential functional DNA sequence variants, in
particular those rare and structural variants, for male BMD, and to assess their sex/ethnicity generality/specificity
and their ultimate importance to the most devastating clinical outcome of OP - osteoporotic hip fracture (HF).
 During the past ~two decades, we have 1) recruited one of the largest samples in the field; 2) established broad
collaboration; 3) assembled an experienced team with extensive multi-disciplinary research productivity.
 In this project, we propose to capitalize on our unique extensive resources to fulfill the following Specific Aims:
 Aim 1. Identify (Discovery) potential functional variants for male OP risk by whole-genome sequencing
 We will perform a large-scale whole-genome sequencing (WGS) to search for functional variants associated with
BMD in 3,200 unrelated US Caucasian males with extremely discordant hip BMDs (1,600 with high and 1,600 with
low hip BMD). To further increase the power, we will perform WGS imputation (for common & rare variants) in
>6,500 independent male subjects (used in our earlier GWAS) for combined analyses with the WGS data.
 Aim 2. Validate promising functional variants discovered in Aim 1 and identify those sex-specific ones
 We will validate the 200 top variants identified above in an independent sample of 12,000 US Caucasians (both
males and females). Sex-specific or sex-general effects of these variants will be assessed.
 Aim 3. Assess ethnicity/population-generality/specificity of the identified variants
 Ethnicity/population-generality/specificity of the top ~50 most significant variants validated in Aim 2 will be tested
in ~85,000 subjects, including Caucasians, African Americans, Hispanic Americans, and East Asians.
 Aim 4. Test the identified BMD variants for their relevance to HF
 We will test at least 20 top BMD variants validated in Aim 2 for their relevance to HF, in the world largest collection
of an independent sample of 10,493 HF cases and 10,815 matched controls.
 Data from this project will be examined integratively with other functional omics data from Proj 2&3 (transcriptome
and epigenome) in this U19 program project and from our proteomics project (R01AR057049, PI Dr. Deng). The
purposes are to 1) gain insights into the potential functional mechanisms of the variants/genes identified in this
project, 2) identify additional significant functional variants/genes by synthesizing various omics data. Regular eQTL
(exp...

## Key facts

- **NIH application ID:** 10180818
- **Project number:** 5U19AG055373-05
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** HONG-WEN DENG
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $724,943
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180818

## Citation

> US National Institutes of Health, RePORTER application 10180818, Project 1: Genome Wide Sequencing for Osteoporosis Risk Genes in Males (5U19AG055373-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180818. Licensed CC0.

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