School of Medicine and Health Sciences Poster Presentations

Title

Validation of a Genetic Risk Score Based on Single Nucleotide Polymorphisms Implicated in Adult Bone Fragility and Associated with Pediatric Bone Density

Document Type

Poster

Keywords

Genetic Risk Score; Bone Quality; Fracture

Publication Date

Spring 2017

Abstract

BACKGROUND: Osteoporosis and associated fragility fractures are a major health concern in

the United States. 1 in 2 women and 1 in 4 men will suffer a fragility fracture in their lifetime.

Depending on the skeletal site, peak bone mineral density (BMD) is not attained until at least

early adulthood, thus it is possible that with early identification and optimization of modifiable

factors, the incidence of osteoporosis and its damaging effects can be mitigated.

OBJECTIVE: We set out to validate a genetic risk score (GRS) comprised of 63 SNPs

associated with adult bone fragility and/or low BMD, previously shown to be significantly

associated with BMD z-score in children in two previous studies. Our goal was to assess whether

application of the GRS could be extended to include a wider range of age and bone phenotypes.

METHODS: Data from three cohorts were included in our analysis. Two cohorts were

comprised of healthy Caucasian young adults, and one of African American children. SNPs were

genotyped using Illumina Multi-Ethnic Genotyping Arrays (MEGA), with data quality checks

performed in Genome Studio and Plink. Phenotypes analyzed vary by cohort, and include BMD

measures from DXA, as well as relatively novel measures such as robustness. The GRS was

calculated for each subject as a percentage of risk alleles. To assess any relationship to bone

phenotypes, linear regression models were performed in gender specific cohort and with age

added as a covariate.

RESULTS: None of the phenotypes evaluated showed a significant linear relationship with the GRS at the 0.05 significance level, but the relationship between GRS and BMD appeared to trend toward significance in the cohort whose subjects were most like those analyzed in previous studies. Our other cohorts offered an opportunity to discover novel GRS-bone relationships such as robustness, and to test the GRS for the first time in an African American cohort, so it was not surprising to us that no relationships were found. Further investigation will focus on why the GRS was unable to predict BMD in our cohorts.

DISCUSSION: While our study was not able to validate the use of the GRS as a tool to predict measures of bone quality, we did find some interesting patterns showing differences between genders and between those of differing ethnic backgrounds. These factors will be important to consider as the GRS strives to become a clinically useful tool.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Open Access

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Comments

Poster to be presented at GW Annual Research Days 2017.

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Validation of a Genetic Risk Score Based on Single Nucleotide Polymorphisms Implicated in Adult Bone Fragility and Associated with Pediatric Bone Density

BACKGROUND: Osteoporosis and associated fragility fractures are a major health concern in

the United States. 1 in 2 women and 1 in 4 men will suffer a fragility fracture in their lifetime.

Depending on the skeletal site, peak bone mineral density (BMD) is not attained until at least

early adulthood, thus it is possible that with early identification and optimization of modifiable

factors, the incidence of osteoporosis and its damaging effects can be mitigated.

OBJECTIVE: We set out to validate a genetic risk score (GRS) comprised of 63 SNPs

associated with adult bone fragility and/or low BMD, previously shown to be significantly

associated with BMD z-score in children in two previous studies. Our goal was to assess whether

application of the GRS could be extended to include a wider range of age and bone phenotypes.

METHODS: Data from three cohorts were included in our analysis. Two cohorts were

comprised of healthy Caucasian young adults, and one of African American children. SNPs were

genotyped using Illumina Multi-Ethnic Genotyping Arrays (MEGA), with data quality checks

performed in Genome Studio and Plink. Phenotypes analyzed vary by cohort, and include BMD

measures from DXA, as well as relatively novel measures such as robustness. The GRS was

calculated for each subject as a percentage of risk alleles. To assess any relationship to bone

phenotypes, linear regression models were performed in gender specific cohort and with age

added as a covariate.

RESULTS: None of the phenotypes evaluated showed a significant linear relationship with the GRS at the 0.05 significance level, but the relationship between GRS and BMD appeared to trend toward significance in the cohort whose subjects were most like those analyzed in previous studies. Our other cohorts offered an opportunity to discover novel GRS-bone relationships such as robustness, and to test the GRS for the first time in an African American cohort, so it was not surprising to us that no relationships were found. Further investigation will focus on why the GRS was unable to predict BMD in our cohorts.

DISCUSSION: While our study was not able to validate the use of the GRS as a tool to predict measures of bone quality, we did find some interesting patterns showing differences between genders and between those of differing ethnic backgrounds. These factors will be important to consider as the GRS strives to become a clinically useful tool.