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

The 313-variant polygenic risk score (PRS) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS 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 PRS differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS 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.