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Ethnic disparities in fracture risk assessment using polygenic scores

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Abstract

Summary

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, \({\mathrm{PGS}\_\mathrm{TB}}_{\mathrm{ldpred}}\) performed the best. A standard deviation decreases in \({\mathrm{PGS}\_\mathrm{TB}}_{\mathrm{ldpred}}\) 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.

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Data availability

Data sharing does not apply to this article as no datasets were generated during the current study.

Abbreviations

BMD:

Bone mineral density

PGS:

Polygenic score

GWAS:

Genome-wide association study

FRAX:

Fracture risk assessment tool

SNP:

Single nucleotide polymorphisms

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Acknowledgements

The study was supported by the National Institute of General Medical Sciences under award number P20GM121325 and by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under award number R21MD013681. In addition, the National Supercomputing Institute at the University of Nevada, Las Vegas, provided facilities for bioinformatical analysis in this study. Part of Dr. Qing Wu’s work was completed at the Nevada Institute of Personalized Medicine, College of Sciences, Department of Epidemiology and Biostatistics, School of Public Health, University of Nevada, Las Vegas.

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  1. Nevada Institute of Personalized Medicine, College of Science, University of Nevada, Las Vegas, NV, USA

    Xiangxue Xiao

  2. Department of Epidemiology and Biostatistics, School of Public Health, University of Nevada Las Vegas, Las Vegas, NV, USA

    Xiangxue Xiao

  3. Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320K Lincoln Tower, 1800 Cannon Dr., Columbus, OH, 43210, USA

    Qing Wu

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  1. Xiangxue Xiao
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Correspondence to Qing Wu.

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This research work was approved by the UK Biobank and the institutional review board at the University of Nevada, Las Vegas. This study has been conducted using the UK Biobank Data Resource under application number 58122.

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Xiao, X., Wu, Q. Ethnic disparities in fracture risk assessment using polygenic scores. Osteoporos Int 34, 943–953 (2023). https://doi.org/10.1007/s00198-023-06712-y

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