Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction

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 P, 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 PD, Simard J, Antoniou AC, Easton DF, Michailidou K (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 26

Article Number: 189

Journal Issue: 1

DOI: 10.1186/s13058-024-01947-x

Abstract

Background: The 313-variant polygenic risk score (PRS313) 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.

Authors with CRIS profile

Involved external institutions

University of Cambridge United Kingdom (GB) Cyprus Institute of Neurology and Genetics Cyprus (CY) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) National Cancer Institute (NCI) United States (USA) (US) Lunenfeld-Tanenbaum Research Institute Canada (CA) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Queen's University Canada (CA) Lund University / Lunds universitet Sweden (SE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) The Institute of Cancer Research (ICR) United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Mayo Clinic United States (USA) (US) American Cancer Society United States (USA) (US) Gentofte Hospital Denmark (DK) Harvard T.H. Chan School of Public Health United States (USA) (US) University of Utah United States (USA) (US) Instituto de Investigación Sanitaria Galicia Sur Spain (ES) Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Germany (DE) Intermountain Healthcare United States (USA) (US) University of Oslo Norway (NO) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Oulun Yliopisto / University of Oulo Finland (FI) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) Technion - Israel Institute of Technology Israel (IL) University of Manchester United Kingdom (GB) Karolinska Institute Sweden (SE) Universität Leipzig Germany (DE) Curtin University Australia (AU) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) University College London (UCL) United Kingdom (GB) Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP) France (FR) Universitätsklinikum Köln Germany (DE) Keck School of Medicine of USC United States (USA) (US) University of Eastern Finland Finland (FI) Université de Montréal Canada (CA) Erasmus University Medical Center (MC) Netherlands (NL) City of Hope Medical Center United States (USA) (US) Carmel Medical Center Israel (IL) University General Hospital of Heraklion Greece (GR) University of British Columbia Canada (CA) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) Finland (FI) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Memorial Sloan Kettering Cancer Center United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Brigham and Women's Hospital (BWH) United States (USA) (US) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov" (RCGEB) Republic of North Macedonia (MK) Monash University Australia (AU) Melbourne School of Population and Global Health Australia (AU) National Institute of Environmental Health Sciences (NIEHS) United States (USA) (US) Hospital Universitario Puerta de Hierro - Majadahonda Spain (ES) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) General University Hospital of Larissa Greece (GR) King’s College London United Kingdom (GB) Vanderbilt University Medical Center United States (USA) (US) University of California Irvine United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Boston Children's Hospital United States (USA) (US) University of Sheffield United Kingdom (GB) Fox Chase Cancer Center United States (USA) (US) Leiden University Medical Center Netherlands (NL) University of Southampton United Kingdom (GB) Universitätsklinikum Düsseldorf Germany (DE) Cedars-Sinai Medical Center United States (USA) (US) CHU de Québec-Université Laval Canada (CA)

How to cite

APA:

Yiangou, K., Mavaddat, N., Dennis, J., Zanti, M., Wang, Q., Bolla, M.K.,... Michailidou, K. (2024). Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction. Breast Cancer Research, 26(1). https://doi.org/10.1186/s13058-024-01947-x

MLA:

Yiangou, Kristia, et al. "Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction." Breast Cancer Research 26.1 (2024).

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