School of Medicine and Health Sciences Poster Presentations
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
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Open Access
1
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.
Comments
Poster to be presented at GW Annual Research Days 2017.