The Clinical Utility of the BMD-related comprehensive Genome-wide polygenic score in identifying individuals with a high risk of osteoporotic fractures

Abstract

Purpose: This study sought to construct genome-wide polygenic scores for femoral neck and total body BMD and to estimate their potential in identifying individuals with a high risk of osteoporotic fractures. Methods: Genome-wide polygenic scores were developed and validated for femoral neck and total body BMD. We externally tested the PGSs, both by themselves and in combination with available clinical risk factors, in 455,663 European ancestry individuals from the UK Biobank. The predictive accuracy of the developed genome-wide PGS was also compared with previously published restricted PGS employed in fracture risk assessment. Results: For each unit decrease in PGSs, the genome-wide PGSs were associated with up to a 1.17-fold increased fracture risk. Out of four studied PGSs, PGS_TBBMD_81 (HR: 1.03; 95%CI 1.01-1.05, p=0.001) had the weakest and the PGS_TBBMD_ldpred (HR: 1.17; 95%CI 1.15-1.19, p<0.0001) had the strongest association with an incident fracture. In the reclassification analysis, compared to the FRAX base model, the models with, PGS_FNBMD_63, PGS_TBBMD_81, PGS_FNBMD_ldpred, and PGS_TBBMD_ldpred improved the reclassification of fracture by 2% (95% CI, 1.5% to 2.4%), 0.2% (95% CI, 0.1% to 0.3%), 1.4% (95% CI, 1.3% to 1.5%), and 2.2% (95% CI, 2.1% to 2.4%), respectively. Conclusions: Our findings suggested that an efficient PGS estimate enables the identification of strata with up to a 1.5-fold difference in fracture incidence. Incorporating PGS information into clinical diagnosis is anticipated to increase the benefits of screening programs at the population level.

Validation of a genome-wide polygenic score in improving fracture risk assessment beyond the FRAX tool in the Women’s Health Initiative study

“…Implementing individual-level genome-wide PGSs summarizing the underlying genetic predisposition of certain diseases in the clinical setting holds excellent promise. Previously, we developed and internally validated two genome-wide BMD-related PGSs using data from the UKB cohort [ 17 ]. Our findings indicated that both PGSs were significantly associated with incident fractures, even after being adjusted for FRAX clinical risk factors [ 17 ].…”

“…Previously, we developed and internally validated two genome-wide BMD-related PGSs using data from the UKB cohort [ 17 ]. Our findings indicated that both PGSs were significantly associated with incident fractures, even after being adjusted for FRAX clinical risk factors [ 17 ]. In the current study, we replicated the two BMD-associated PGSs from previous work [ 17 ] and additionally derived a third PGS—metaPGS combining the effect of the two established PGSs and evaluated their predictive effect in an independent WHI postmenopausal women sample.…”

“…PGS _ FNBMD ldpred and PGS _ TBBMD ldpred were quantified using LDpred2 with optimal hyperparameters determined previously [ 17 ]. For femoral neck BMD and total body BMD, ρ thresholds of 0.03 and 0.13, respectively, were used to derive the genome-wide PGSs for each individual in the WHI cohort.…”

“…Moreover, extensive cohort resources have enabled the genetic prediction of such heritable clinical risk factors from genotypes through polygenic scores (PGS), which capture information from many single nucleotide polymorphisms (SNPs) assayed from genome-wide genotyping. We previously developed and validated two genome-wide PGSs related to the femoral neck ( PGS _ FNBMD ldpred ) and total body BMD ( PGS _ TBBMD ldpred ) in the UK Biobank (UKB) cohort [ 17 ]. Both genome-wide PGS was proven to be significantly associated with incident fracture risk, even after accounting for FRAX clinical risk factors [ 17 ] However, the UKB participants were generally younger and healthier than the general population.…”

“…We previously developed and validated two genome-wide PGSs related to the femoral neck ( PGS _ FNBMD ldpred ) and total body BMD ( PGS _ TBBMD ldpred ) in the UK Biobank (UKB) cohort [ 17 ]. Both genome-wide PGS was proven to be significantly associated with incident fracture risk, even after accounting for FRAX clinical risk factors [ 17 ] However, the UKB participants were generally younger and healthier than the general population. Our prior findings thus lack generalizability outside of the UKB cohort.…”