Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction

Abstract

The 313-variant polygenic risk score (PRS₃₁₃) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS₃₁₃ across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS₃₁₃ across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS₃₁₃ differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS₃₁₃ distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

Figure 1:

Map of the European countries of origin of BCAC study participants included in the analysis. Countries were coloured based on their mean standardized PRS₃₁₃ in control dataset of BCAC. Countries with higher mean are represented with darker colour while those with lower mean with lighter colour.

Figure 2:

Distribution of the standardized PRS₃₁₃ across country of origin for overall, ER-positive and ER-negative breast cancer in control dataset of BCAC. The squares represent the mean PRS by country and the error bars represent the corresponding 95% confidence intervals (FE Model: Fixed effect Model).

Figure 3:

Distribution of the mean PRS₃₀₆, and “standard” PRS for breast cancer, as defined in the UK Biobank, across countries of origin of participating white females. The squares represent the mean PRS by country and the error bars represent the corresponding 95% confidence intervals (FE Model: Fixed effect Model).

Figure 4:

PRS₃₁₃ distribution in controls by percentiles in the pooled BCAC dataset, Greece, Ireland and Italy. The dashed line corresponds to the 95th percentile of the PRS₃₁₃ distribution in controls of the pooled BCAC dataset.

Figure 5:

Classification of a 50-year-old woman from Greece when her raw PRS₃₁₃, which is equal to 0.34 is standardized based on the mean and SD of the controls of BOADICEA model (upper panel) and Greece (lower panel), using the CanRisk tool. Plots were generated using the CanRisk tool (www.canrisk.org).

Figure 6:

Classification of a 50-year-old woman from Ireland when her raw PRS₃₁₃, which is equal to 0.27 is standardized based on the mean and SD of the controls BOADICEA (upper panel) model and Ireland (lower panel), using the CanRisk tool. Plots were generated using the CanRisk tool (www.canrisk.org).