Ethnic disparities in fracture risk assessment using polygenic scores

Abstract

Whether the PGS developed using data from European ancestry is predictive of fracture risk for minorities remains unclear. This study demonstrated that PGSs based on common BMD-related genetic variants discovered in the European ancestry cohort are predictive of fracture risk in people of Asian but not African ancestry.

Purpose: Large-scale genome-wide association studies (GWAS) on bone mineral density (BMD) have been conducted predominantly in European cohorts. Genetic models based on common variants associated with BMD have been evaluated using almost exclusively European data, which could potentially exacerbate health disparities due to different linkage disequilibrium among different ethnic groups.

Methods: UK Biobank (UKB) is a large-scale population-based observational study starting in 2006 that recruited 502,617 individuals aged between 40 and 69 years with genotypic and phenotypic data available. Based on the summary statistics of two GWAS studies of femoral neck BMD and total body BMD, we derived four PGSs and assessed the association between each PGS and prevalent/incident fractures within each ethnic group separately using Multivariate logistic regressions and Cox proportional hazard models. All models were adjusted for age, sex, and the first four principal components.

Results: We assessed four PGSs derived from European cohorts. Significant associations were observed between PGSs and fracture in European and Asian cohorts but not in the African cohort. Of all four PGSs, [Formula: see text] performed the best. A standard deviation decreases in [Formula: see text] were associated with an increased hazard ratio (HR) of 1.24 (1.22-1.27), 1.28 (0.83-1.99), and 1.34 (1.10-1.64) in European, African, and Asian ancestry, respectively. A low BMD-related PGS is associated with up to 2.35- and 4.31-fold increased fracture risk in European and Asian populations.

Conclusions: These results showed that PGSs based on common BMD-related genetic variants discovered in the European ancestry cohort are predictive of fracture risk in people of Asian but not African ancestry.

Keywords: Disease and disorders of/related to bone; Fracture risk assessment; Genetic research; Human association studies; Osteoporosis.