Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction
Authors: Yiangou Kristia , Mavaddat Nasim , Dennis Joe , Zanti Maria , Wang Qin , Bolla Manjeet K. , Abubakar Mustapha , Ahearn Thomas U. , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Arndt Volker , Aronson Kristan J. , Augustinsson Annelie , Baten Adinda , Behrens Sabine , Bermisheva Marina , Berrington de Gonzalez Amy , Białkowska Katarzyna , Boddicker Nicholas , Bodelon Clara , Bogdanova Natalia V. , Bojesen Stig E. , Brantley Kristen D. , Brauch Hiltrud , Brenner Hermann , Camp Nicola J. , Canzian Federico , Castelao Jose E. , Cessna Melissa H. , Chang-Claude Jenny , Chenevix-Trench Georgia , Chung Wendy K. ,   NBCS Collaborators, Colonna Sarah V. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Devilee Peter , Dörk Thilo , Dunning Alison M. , Eccles Diana M. , Eliassen A. Heather , Engel Christoph , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Fletcher Olivia , Flyger Henrik , Fritschi Lin , Gago-Dominguez Manuela , Gentry-Maharaj Aleksandra , González-Neira Anna , Guénel Pascal , Hahnen Eric , Haiman Christopher A. , Hamann Ute , Hartikainen Jaana M. , Ho Vikki , Hodge James , Hollestelle Antoinette , Honisch Ellen , Hooning Maartje J. , Hoppe Reiner , Hopper John L. , Howell Sacha , Howell Anthony ,   ABCTB Investigators,   kConFab Investigators, Jakovchevska Simona , Jakubowska Anna , Jernström Helena , Johnson Nichola , Kaaks Rudolf , Khusnutdinova Elza K. , Kitahara Cari M. , Koutros Stella , Kristensen Vessela N. , Lacey James V. , Lambrechts Diether , Lejbkowicz Flavio , Lindblom Annika , Lush Michael , Mannermaa Arto , Mavroudis Dimitrios , Menon Usha , Murphy Rachel A. , Nevanlinna Heli , Obi Nadia , Offit Kenneth , Park-Simon Tjoung-Won , Patel Alpa V. , Peng Cheng , Peterlongo Paolo , Pita Guillermo , Plaseska-Karanfilska Dijana , Pylkäs Katri , Radice Paolo , Rashid Muhammad U. , Rennert Gad , Roberts Eleanor , Rodriguez Juan , Romero Atocha , Rosenberg Efraim H. , Saloustros Emmanouil , Sandler Dale P. , Sawyer Elinor J. , Schmutzler Rita K. , Scott Christopher G. , Shu Xiao-Ou , Southey Melissa C. , Stone Jennifer , Taylor Jack A. , Teras Lauren R. , van de Beek Irma , Willett Walter , Winqvist Robert , Zheng Wei , Vachon Celine M. , Schmidt Marjanka K. , Hall Per , MacInnis Robert J. , Milne Roger L. , Pharoah Paul D.P. , Simard Jacques , Antoniou Antonis C. , Easton Douglas F. , Michailidou Kyriaki 
Published: February 2024

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313across 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 PRS313differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313distribution 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.