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

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.