Identifying Rare Genetic Determinants for Improved Polygenic Risk Prediction of Bone Mineral Density and Fracture Risk
Authors' conclusion
In summary, modeling the effects of rare genetic determinants may assist polygenic prediction of fracture risk among carriers of influential rare variants.
Study context
- Population
- UK Biobank participants with whole-exome sequencing; White British training and test sets; also non-White British European, African, East Asian, South Asian and other admixed ancestriesUK Biobank · White British training 317,434 · test 74,825 · also non-White British European 18,885 · African 7,165 · East Asian 2,236 · South Asian 9,829 · other admixed 1,481
- Participants
- 436,824 participants
- Comparison
- ggSOS vs common variant-based PRS
- Outcome
- Prediction of major osteoporotic fracture (C-index), White British test set
Methodological detailswhole-exome sequencing, training and test data sets, gene burden testing
- Whole-exome sequencing
- Training and test data sets
- Gene burden testing
Main finding
As reported in the abstract
ggSOS
0.644
C-index
Common variant-based PRS
0.641
C-index
Further findings
| Outcome | HR (95% CI) | |
|---|---|---|
| Major osteoporotic fracture per 1 SD decrease in ggSOS among rare-variant carriers in test set4013 (5.4%) carriers | 1.35 (1.16–1.57) | |
| 0.512Hazard ratio (log scale) |
Genes harbouring influential rare variants associated with speed of sound (SOS)
- Genes with influential rare variants associated with SOS (p < 5.5 × 10-7 ): AHNAK, BMP5, CYP19A1, FAM20A, FBXW5, KDM5B, KREMEN1, LGR4, LRP5, SMAD6, SOST, WNT1
- 12
Predictive performance in non-European ancestry populations
- ggSOS did not demonstrate substantially improved predictive performance
Original publication
Identifying Rare Genetic Determinants for Improved Polygenic Risk Prediction of Bone Mineral Density and Fracture Risk. J Bone Miner Res. Published 26 October 2023. doi:10.
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