Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture

Abstract

Low bone mineral density (BMD) leads to osteoporosis, and is a risk factor for bone fractures, including stress fractures. Using data from UK Biobank, a genome-wide association study identified 1,362 independent SNPs that clustered into 899 loci of which 613 are new. These data were used to train a genetic algorithm using 22,886 SNPs as predictors and showing a correlation with heel bone mineral density of 0.415. Combining this genetic algorithm with height, weight, age and sex resulted in a correlation with heel bone mineral density of 0.496. Individuals with low scores (2.2% of total) showed a change in BMD of -1.16 T-score units, an increase in risk for osteoporosis of 17.4 fold and an increase in risk for fracture of 1.87 fold. Genetic predictors could assist in the identification of individuals at risk for osteoporosis or fractures.

Fig 1. Quantile-quantile plot for genome-wide association analysis of eBMD.

The expected versus observed log transformed values for the 20,259,828 p-values from the LMM analysis are graphed. The y-axis shows the observed p-values and the x-axis shows the p-values expected by chance. The black dots represent the SNPs arranged by their observed p-values and the red line shows the expected trajectory if the SNPs had p-values expected by chance.

Fig 2. Manhattan plot for genome-wide association analysis of eBMD.

The -log₁₀ p-values for association with eBMD of SNPs from the LMM analysis are plotted by genomic position with chromosome number listed across the bottom. The y-axis shows the -log₁₀ p-value for association with eBMD. The blue line represents suggestive genome-wide significance (p<5x10^-5) and the red line represents genome-wide significance (p<6.6x10^-9).

Fig 3. Regional-association plots for eBMD.

A. Locus 385. B. Locus 324. C. Locus 336. D. Locus 89. Tested SNPs are arranged by genomic position (x-axis) around the lead SNP (purple diamond). The y-axis on the left indicates -log₁₀ p-values for association with eBMD for each SNP. The y-axis on the right indicates recombination rate shown with a blue line. The color of dots of the flanking SNPs indicates their linkage disequilibrium (R²) with the lead SNP as indicated by the heat map color key.

Fig 4. Relationship between effect size and minor allele frequency.

Shown is a scatterplot of 1362 SNPs with an independent association with eBMD. The x-axis is the minor allele frequency. The y-axis is the absolute value of the beta coefficient from the joint and conditional analysis.

Fig 5. Analysis of predictors used in LASSO4.

A. Histogram of p-values used by predictors in LASSO4. X-axis shows the–Log₁₀ of the p-value for association with eBMD from cohort A, from p = 10⁻² to p = 10⁻⁸. Inset shows data for all p-values used in LASSO4. B. Plot of cumulative score from predictors in LASSO4. X-axis is a running total of number of predictors and y-axis is the cumulative score (T-score units) from those predictors.

Fig 6. Prediction of eBMD, osteoporosis risk and fracture risk using the LASSO4 score.

A. Comparison of LASSO4 with A. eBMD, B. osteoporosis risk and C. fracture risk. Individuals from cohort C were ranked based on their risk score and placed into bins. Red dots show average eBMD (T score), osteoporosis risk and fracture risk (left y-axes). Gray bars show number of individuals in each bin (right y-axis). Lowest risk score for each bin is shown on the x-axis. Error bars indicate 95% confidence intervals.

Fig 7. Prediction of eBMD, osteoporosis risk and fracture risk using the BOG score.

A. Comparison of the BOG risk score with A. eBMD, B. osteoporosis risk and C. fracture risk. Individuals from cohort C were ranked based on their risk score and placed into bins. Red dots show average eBMD (T score), osteoporosis risk and fracture risk (left y-axes). Gray bars show number of individuals in each bin (right y-axis). Risk score for each bin is shown on the x-axis. Error bars indicate 95% confidence intervals.

Fig 8. Receiver Operator and box plots for PRS’s for osteoporosis risk.

A. Receiver Operator plot for the LASSO4 PRS for osteoporosis. B. Box plot for the LASSO 4 PRS. C. Receiver Operator curve for the BOG score for osteoporosis. D. Box plot for the BOG score. AUC; Area Under the Curve. Box plots show the maximum, first quartile, mean, third quartile and minimum scores for LASSO4 and BOG for osteoporosis cases and controls.