1. Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.
- Author
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Yiangou K, Mavaddat N, Dennis J, Zanti M, Wang Q, Bolla MK, Abubakar M, Ahearn TU, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Augustinsson A, Baten A, Behrens S, Bermisheva M, de Gonzalez AB, Białkowska K, Boddicker N, Bodelon C, Bogdanova NV, Bojesen SE, Brantley KD, Brauch H, Brenner H, Camp NJ, Canzian F, Castelao JE, Cessna MH, Chang-Claude J, Chenevix-Trench G, Chung WK, Colonna SV, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dunning AM, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Flyger H, Fritschi L, Gago-Dominguez M, Gentry-Maharaj A, González-Neira A, Guénel P, Hahnen E, Haiman CA, Hamann U, Hartikainen JM, Ho V, Hodge J, Hollestelle A, Honisch E, Hooning MJ, Hoppe R, Hopper JL, Howell S, Howell A, Jakovchevska S, Jakubowska A, Jernström H, Johnson N, Kaaks R, Khusnutdinova EK, Kitahara CM, Koutros S, Kristensen VN, Lacey JV, Lambrechts D, Lejbkowicz F, Lindblom A, Lush M, Mannermaa A, Mavroudis D, Menon U, Murphy RA, Nevanlinna H, Obi N, Offit K, Park-Simon TW, Patel AV, Peng C, Peterlongo P, Pita G, Plaseska-Karanfilska D, Pylkäs K, Radice P, Rashid MU, Rennert G, Roberts E, Rodriguez J, Romero A, Rosenberg EH, Saloustros E, Sandler DP, Sawyer EJ, Schmutzler RK, Scott CG, Shu XO, Southey MC, Stone J, Taylor JA, Teras LR, van de Beek I, Willett W, Winqvist R, Zheng W, Vachon CM, Schmidt MK, Hall P, MacInnis RJ, Milne RL, Pharoah PDP, Simard J, Antoniou AC, Easton DF, and Michailidou K
- Subjects
- Humans, Female, Risk Assessment methods, Risk Factors, Europe epidemiology, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Middle Aged, Genotype, Breast Neoplasms genetics, Breast Neoplasms epidemiology, Genetic Predisposition to Disease, Multifactorial Inheritance, White People genetics
- Abstract
Background: The 313-variant polygenic risk score (PRS
313 ) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed., Methods: We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction., Results: The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment., Conclusions: Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories., Competing Interests: Declarations. Ethics approval and consent to participate: All study participants gave written informed consent, and all the Breast Cancer Association Consortium studies were approved by the relevant ethics committees. The Breast Cancer Association Consortium data have been used under the application with access number 712. The use of the UK Biobank has been approved under application ID102655. Consent for publication: Not applicable. Competing interests: The following authors declare conflicts not directly relevant to this work as stated below: U.M. has a patent (no: EP10178345.4) for Breast Cancer Diagnostics and held personal shares in Abcodia Ltd between 2011 and 2021. She has research collaborations with Mercy Bioanalytics, iLOF, RNA Guardian and Micronoma in the field of early detection of cancer. P.A.F. conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. R.A.M. is a Consultant for Pharmavite., (© 2024. The Author(s).)- Published
- 2024
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