Identifying rare genetic determinants for improved polygenic risk prediction of bone mineral density and fracture risk

J Bone Miner Res. 2023 Oct 13. doi: 10.1002/jbmr.4920. Online ahead of print.

ABSTRACT

Osteoporosis and fractures severely impact the elderly population. Polygenic risk scores for bone mineral density have demonstrated potential clinical utility. However, the value of rare genetic determinants in risk prediction has not been assessed. With whole-exome sequencing data from 436,824 UK Biobank participants, we assigned White British ancestry individuals into a training dataset (N = 317,434) and a test dataset (N = 74,825). In the training dataset, we developed a common variant-based polygenic risk score for heel ultrasound speed of sound (SOS). Next, we performed burden testing to identify genes harboring rare determinants of bone mineral density, targeting influential rare variants with predicted high deleteriousness. We constructed a genetic risk score, called ggSOS, to incorporate influential rare variants in significant gene burden masks into the common variant-based polygenic risk score. We assessed the predictive performance of ggSOS in the White British test dataset, as well as in populations of non-White British European (N = 18,885), African (N = 7165), East Asian (N = 2236), South Asian (N = 9829), and other admixed (N = 1481) ancestries. Twelve genes in pivotal regulatory pathways of bone homeostasis harbored influential rare variants associated with SOS (p-value<5.5x10^-7 ), including AHNAK, BMP5, CYP19A1, FAM20A, FBXW5, KDM5B, KREMEN1, LGR4, LRP5, SMAD6, SOST, and WNT1. Amongst 4013 (5.4%) individuals in the test dataset carrying these variants, a one standard deviation decrease in ggSOS was associated with 1.35-fold (95% CI:1.16-1.57) increased hazard of major osteoporotic fracture. However, compared to a common variant-based polygenic risk score (C-index = 0.641), ggSOS had only marginally improved prediction accuracy in identifying at-risk individuals (C-index = 0.644), with overlapping confidence intervals. Similarly, ggSOS did not demonstrate substantially improved predictive performance in non-European ancestry populations. In summary, modelling the effects of rare genetic determinants may assist polygenic prediction of fracture risk amongst carriers of influential rare variants. Nonetheless, improved clinical utility is not guaranteed for population-level risk screening. This article is protected by copyright. All rights reserved.

PMID:37830501 | DOI:10.1002/jbmr.4920