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

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 distri...

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Main Authors: Kristia Yiangou, Nasim Mavaddat, Joe Dennis, Maria Zanti, Qin Wang, Manjeet K. Bolla, Mustapha Abubakar, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Adinda Baten, Sabine Behrens, Marina Bermisheva, Amy Berrington de Gonzalez, Katarzyna Białkowska, Nicholas Boddicker, Clara Bodelon, Natalia V. Bogdanova, Stig E. Bojesen, Kristen D. Brantley, Hiltrud Brauch, Hermann Brenner, Nicola J. Camp, Federico Canzian, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Alison M. Dunning, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Manuela Gago-Dominguez, Aleksandra Gentry-Maharaj, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Ute Hamann, Jaana M. Hartikainen, Vikki Ho, James Hodge, Antoinette Hollestelle, Ellen Honisch, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Sacha Howell, Anthony Howell, ABCTB Investigators, kConFab Investigators, Simona Jakovchevska, Anna Jakubowska, Helena Jernström, Nichola Johnson, Rudolf Kaaks, Elza K. Khusnutdinova, Cari M. Kitahara, Stella Koutros, Vessela N. Kristensen, James V. Lacey, Diether Lambrechts, Flavio Lejbkowicz, Annika Lindblom, Michael Lush, Arto Mannermaa, Dimitrios Mavroudis, Usha Menon, Rachel A. Murphy, Heli Nevanlinna, Nadia Obi, Kenneth Offit, Tjoung-Won Park-Simon, Alpa V. Patel, Cheng Peng, Paolo Peterlongo, Guillermo Pita, Dijana Plaseska-Karanfilska, Katri Pylkäs, Paolo Radice, Muhammad U. Rashid, Gad Rennert, Eleanor Roberts, Juan Rodriguez, Atocha Romero, Efraim H. Rosenberg, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Christopher G. Scott, Xiao-Ou Shu, Melissa C. Southey, Jennifer Stone, Jack A. Taylor, Lauren R. Teras, Irma van de Beek, Walter Willett, Robert Winqvist, Wei Zheng, Celine M. Vachon, Marjanka K. Schmidt, Per Hall, Robert J. MacInnis, Roger L. Milne, Paul D. P. Pharoah, Jacques Simard, Antonis C. Antoniou, Douglas F. Easton, Kyriaki Michailidou
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Language:English
Published: BMC 2024-12-01
Series:Breast Cancer Research
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Online Access:https://doi.org/10.1186/s13058-024-01947-x
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author Kristia Yiangou
Nasim Mavaddat
Joe Dennis
Maria Zanti
Qin Wang
Manjeet K. Bolla
Mustapha Abubakar
Thomas U. Ahearn
Irene L. Andrulis
Hoda Anton-Culver
Natalia N. Antonenkova
Volker Arndt
Kristan J. Aronson
Annelie Augustinsson
Adinda Baten
Sabine Behrens
Marina Bermisheva
Amy Berrington de Gonzalez
Katarzyna Białkowska
Nicholas Boddicker
Clara Bodelon
Natalia V. Bogdanova
Stig E. Bojesen
Kristen D. Brantley
Hiltrud Brauch
Hermann Brenner
Nicola J. Camp
Federico Canzian
Jose E. Castelao
Melissa H. Cessna
Jenny Chang-Claude
Georgia Chenevix-Trench
Wendy K. Chung
NBCS Collaborators
Sarah V. Colonna
Fergus J. Couch
Angela Cox
Simon S. Cross
Kamila Czene
Mary B. Daly
Peter Devilee
Thilo Dörk
Alison M. Dunning
Diana M. Eccles
A. Heather Eliassen
Christoph Engel
Mikael Eriksson
D. Gareth Evans
Peter A. Fasching
Olivia Fletcher
Henrik Flyger
Lin Fritschi
Manuela Gago-Dominguez
Aleksandra Gentry-Maharaj
Anna González-Neira
Pascal Guénel
Eric Hahnen
Christopher A. Haiman
Ute Hamann
Jaana M. Hartikainen
Vikki Ho
James Hodge
Antoinette Hollestelle
Ellen Honisch
Maartje J. Hooning
Reiner Hoppe
John L. Hopper
Sacha Howell
Anthony Howell
ABCTB Investigators
kConFab Investigators
Simona Jakovchevska
Anna Jakubowska
Helena Jernström
Nichola Johnson
Rudolf Kaaks
Elza K. Khusnutdinova
Cari M. Kitahara
Stella Koutros
Vessela N. Kristensen
James V. Lacey
Diether Lambrechts
Flavio Lejbkowicz
Annika Lindblom
Michael Lush
Arto Mannermaa
Dimitrios Mavroudis
Usha Menon
Rachel A. Murphy
Heli Nevanlinna
Nadia Obi
Kenneth Offit
Tjoung-Won Park-Simon
Alpa V. Patel
Cheng Peng
Paolo Peterlongo
Guillermo Pita
Dijana Plaseska-Karanfilska
Katri Pylkäs
Paolo Radice
Muhammad U. Rashid
Gad Rennert
Eleanor Roberts
Juan Rodriguez
Atocha Romero
Efraim H. Rosenberg
Emmanouil Saloustros
Dale P. Sandler
Elinor J. Sawyer
Rita K. Schmutzler
Christopher G. Scott
Xiao-Ou Shu
Melissa C. Southey
Jennifer Stone
Jack A. Taylor
Lauren R. Teras
Irma van de Beek
Walter Willett
Robert Winqvist
Wei Zheng
Celine M. Vachon
Marjanka K. Schmidt
Per Hall
Robert J. MacInnis
Roger L. Milne
Paul D. P. Pharoah
Jacques Simard
Antonis C. Antoniou
Douglas F. Easton
Kyriaki Michailidou
author_facet Kristia Yiangou
Nasim Mavaddat
Joe Dennis
Maria Zanti
Qin Wang
Manjeet K. Bolla
Mustapha Abubakar
Thomas U. Ahearn
Irene L. Andrulis
Hoda Anton-Culver
Natalia N. Antonenkova
Volker Arndt
Kristan J. Aronson
Annelie Augustinsson
Adinda Baten
Sabine Behrens
Marina Bermisheva
Amy Berrington de Gonzalez
Katarzyna Białkowska
Nicholas Boddicker
Clara Bodelon
Natalia V. Bogdanova
Stig E. Bojesen
Kristen D. Brantley
Hiltrud Brauch
Hermann Brenner
Nicola J. Camp
Federico Canzian
Jose E. Castelao
Melissa H. Cessna
Jenny Chang-Claude
Georgia Chenevix-Trench
Wendy K. Chung
NBCS Collaborators
Sarah V. Colonna
Fergus J. Couch
Angela Cox
Simon S. Cross
Kamila Czene
Mary B. Daly
Peter Devilee
Thilo Dörk
Alison M. Dunning
Diana M. Eccles
A. Heather Eliassen
Christoph Engel
Mikael Eriksson
D. Gareth Evans
Peter A. Fasching
Olivia Fletcher
Henrik Flyger
Lin Fritschi
Manuela Gago-Dominguez
Aleksandra Gentry-Maharaj
Anna González-Neira
Pascal Guénel
Eric Hahnen
Christopher A. Haiman
Ute Hamann
Jaana M. Hartikainen
Vikki Ho
James Hodge
Antoinette Hollestelle
Ellen Honisch
Maartje J. Hooning
Reiner Hoppe
John L. Hopper
Sacha Howell
Anthony Howell
ABCTB Investigators
kConFab Investigators
Simona Jakovchevska
Anna Jakubowska
Helena Jernström
Nichola Johnson
Rudolf Kaaks
Elza K. Khusnutdinova
Cari M. Kitahara
Stella Koutros
Vessela N. Kristensen
James V. Lacey
Diether Lambrechts
Flavio Lejbkowicz
Annika Lindblom
Michael Lush
Arto Mannermaa
Dimitrios Mavroudis
Usha Menon
Rachel A. Murphy
Heli Nevanlinna
Nadia Obi
Kenneth Offit
Tjoung-Won Park-Simon
Alpa V. Patel
Cheng Peng
Paolo Peterlongo
Guillermo Pita
Dijana Plaseska-Karanfilska
Katri Pylkäs
Paolo Radice
Muhammad U. Rashid
Gad Rennert
Eleanor Roberts
Juan Rodriguez
Atocha Romero
Efraim H. Rosenberg
Emmanouil Saloustros
Dale P. Sandler
Elinor J. Sawyer
Rita K. Schmutzler
Christopher G. Scott
Xiao-Ou Shu
Melissa C. Southey
Jennifer Stone
Jack A. Taylor
Lauren R. Teras
Irma van de Beek
Walter Willett
Robert Winqvist
Wei Zheng
Celine M. Vachon
Marjanka K. Schmidt
Per Hall
Robert J. MacInnis
Roger L. Milne
Paul D. P. Pharoah
Jacques Simard
Antonis C. Antoniou
Douglas F. Easton
Kyriaki Michailidou
author_sort Kristia Yiangou
collection DOAJ
description 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.
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spelling doaj-art-3c847db3b1ae4ba1ae9f69bedf4ca3ce2024-12-29T12:53:20ZengBMCBreast Cancer Research1465-542X2024-12-0126111410.1186/s13058-024-01947-xPolygenic score distribution differences across European ancestry populations: implications for breast cancer risk predictionKristia Yiangou0Nasim Mavaddat1Joe Dennis2Maria Zanti3Qin Wang4Manjeet K. Bolla5Mustapha Abubakar6Thomas U. Ahearn7Irene L. Andrulis8Hoda Anton-Culver9Natalia N. Antonenkova10Volker Arndt11Kristan J. Aronson12Annelie Augustinsson13Adinda Baten14Sabine Behrens15Marina Bermisheva16Amy Berrington de Gonzalez17Katarzyna Białkowska18Nicholas Boddicker19Clara Bodelon20Natalia V. Bogdanova21Stig E. Bojesen22Kristen D. Brantley23Hiltrud Brauch24Hermann Brenner25Nicola J. Camp26Federico Canzian27Jose E. Castelao28Melissa H. Cessna29Jenny Chang-Claude30Georgia Chenevix-Trench31Wendy K. Chung32NBCS Collaborators33Sarah V. Colonna34Fergus J. Couch35Angela Cox36Simon S. Cross37Kamila Czene38Mary B. Daly39Peter Devilee40Thilo Dörk41Alison M. Dunning42Diana M. Eccles43A. Heather Eliassen44Christoph Engel45Mikael Eriksson46D. Gareth Evans47Peter A. Fasching48Olivia Fletcher49Henrik Flyger50Lin Fritschi51Manuela Gago-Dominguez52Aleksandra Gentry-Maharaj53Anna González-Neira54Pascal Guénel55Eric Hahnen56Christopher A. Haiman57Ute Hamann58Jaana M. Hartikainen59Vikki Ho60James Hodge61Antoinette Hollestelle62Ellen Honisch63Maartje J. Hooning64Reiner Hoppe65John L. Hopper66Sacha Howell67Anthony Howell68ABCTB Investigators69kConFab Investigators70Simona Jakovchevska71Anna Jakubowska72Helena Jernström73Nichola Johnson74Rudolf Kaaks75Elza K. Khusnutdinova76Cari M. Kitahara77Stella Koutros78Vessela N. Kristensen79James V. Lacey80Diether Lambrechts81Flavio Lejbkowicz82Annika Lindblom83Michael Lush84Arto Mannermaa85Dimitrios Mavroudis86Usha Menon87Rachel A. Murphy88Heli Nevanlinna89Nadia Obi90Kenneth Offit91Tjoung-Won Park-Simon92Alpa V. Patel93Cheng Peng94Paolo Peterlongo95Guillermo Pita96Dijana Plaseska-Karanfilska97Katri Pylkäs98Paolo Radice99Muhammad U. Rashid100Gad Rennert101Eleanor Roberts102Juan Rodriguez103Atocha Romero104Efraim H. Rosenberg105Emmanouil Saloustros106Dale P. Sandler107Elinor J. Sawyer108Rita K. Schmutzler109Christopher G. Scott110Xiao-Ou Shu111Melissa C. Southey112Jennifer Stone113Jack A. Taylor114Lauren R. Teras115Irma van de Beek116Walter Willett117Robert Winqvist118Wei Zheng119Celine M. Vachon120Marjanka K. Schmidt121Per Hall122Robert J. MacInnis123Roger L. Milne124Paul D. P. Pharoah125Jacques Simard126Antonis C. Antoniou127Douglas F. Easton128Kyriaki Michailidou129Biostatistics Unit, The Cyprus Institute of Neurology and GeneticsDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeBiostatistics Unit, The Cyprus Institute of Neurology and GeneticsDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of HealthDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of HealthFred A, Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai HospitalDepartment of Medicine, Genetic Epidemiology Research Institute, University of California IrvineNN Alexandrov Research Institute of Oncology and Medical RadiologyDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)Department of Public Health Sciences, and Cancer Research Institute, Queen’s UniversityOncology, Clinical Sciences in Lund, Lund UniversityDepartment of Oncology, Leuven Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals LeuvenDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of SciencesDivision of Genetics and Epidemiology, The Institute of Cancer ResearchDepartment of Genetics and Pathology, Pomeranian Medical UniversityDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Population Science, American Cancer SocietyNN Alexandrov Research Institute of Oncology and Medical RadiologyCopenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University HospitalDepartment of Epidemiology, Harvard TH Chan School of Public HealthDr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)Department of Internal Medicine and Huntsman Cancer Institute, University of UtahGenomic Epidemiology Group, German Cancer Research Center (DKFZ)Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur-Vigo-SpainDepartment of Pathology, Intermountain HealthcareDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)Cancer Research Program, QIMR Berghofer Medical Research InstituteDepartment of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolDepartment of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-RadiumhospitaletDepartment of Internal Medicine and Huntsman Cancer Institute, University of UtahDepartment of Laboratory Medicine and Pathology, Mayo ClinicDivision of Clinical Medicine, School of Medicine and Population Health, University of SheffieldDivision of Neuroscience, School of Medicine and Population Health, University of SheffieldDepartment of Medical Epidemiology and Biostatistics, Karolinska InstitutetDepartment of Clinical Genetics, Fox Chase Cancer CenterDepartment of Pathology, Leiden University Medical CenterGynaecology Research Unit, Hannover Medical SchoolDepartment of Oncology, Centre for Cancer Genetic Epidemiology, University of CambridgeFaculty of Medicine, University of SouthamptonDepartment of Epidemiology, Harvard TH Chan School of Public HealthInstitute for Medical Informatics, Statistics and Epidemiology, University of LeipzigDepartment of Medical Epidemiology and Biostatistics, Karolinska InstitutetDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science CentreDepartment of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital ErlangenThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer ResearchDepartment of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University HospitalSchool of Population Health, Curtin UniversityCancer Genetics and Epidemiology Group, Genomic Medicine Group, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Complejo Hospitalario Universitario de Santiago, SERGASMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College LondonHuman Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO)Team ‘Exposome and Heredity’, CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of CologneDepartment of Preventive Medicine, Keck School of Medicine, University of Southern CaliforniaMolecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)Cancer RC, University of Eastern FinlandHealth Innovation and Evaluation Hub, Université de Montréal Hospital Research Centre (CRCHUM)Department of Population Science, American Cancer SocietyDepartment of Medical Oncology, Erasmus MC Cancer InstituteDepartment of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University DüsseldorfDepartment of Medical Oncology, Erasmus MC Cancer InstituteDr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of MelbourneDivision of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science CentreDivision of Cancer Sciences, University of ManchesterAustralian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of SydneyResearch Department, Peter MacCallum Cancer CenterResearch Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, MASADepartment of Genetics and Pathology, Pomeranian Medical UniversityOncology, Clinical Sciences in Lund, Lund UniversityThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer ResearchDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of SciencesDivision of Cancer Epidemiology and Genetics, National Cancer Institute, NIHDivision of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of HealthInstitute of Clinical Medicine, Faculty of Medicine, University of OsloDepartment of Computational and Quantitative Medicine, City of HopeLaboratory for Translational Genetics, Department of Human Genetics, KU LeuvenCarmel Medical CenterDepartment of Molecular Medicine and Surgery, Karolinska InstitutetDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeInstitute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern FinlandDepartment of Medical Oncology, University Hospital of HeraklionMRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College LondonSchool of Population and Public Health, University of British ColumbiaDepartment of Obstetrics and Gynecology, Helsinki University Hospital, University of HelsinkiInstitute for Occupational and Maritime Medicine, University Medical Center Hamburg-EppendorfClinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer CenterGynaecology Research Unit, Hannover Medical SchoolDepartment of Population Science, American Cancer SocietyChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolGenome Diagnostics Program, IFOM ETS - The AIRC Institute of Molecular OncologyHuman Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO)Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, MASALaboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of OuluUnit of Predictive Medicine, Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT)Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)Technion, Faculty of Medicine and Association for Promotion of Research in Precision MedicineDivision of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science CentreDepartment of Medical Epidemiology and Biostatistics, Karolinska InstitutetMedical Oncology Department, Hospital Universitario Puerta de HierroDepartment of Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek HospitalDepartment of Oncology, University Hospital of LarissaEpidemiology Branch, National Institute of Environmental Health Sciences, NIHSchool of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy’s Campus, King’s College LondonCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of CologneDepartment of Quantitative Health Sciences, Mayo ClinicDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of MedicinePrecision Medicine, School of Clinical Sciences at Monash Health, Monash UniversityCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of MelbourneEpidemiology Branch, National Institute of Environmental Health Sciences, NIHDepartment of Population Science, American Cancer SocietyDepartment of Clinical Genetics, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek HospitalDepartment of Epidemiology, Harvard TH Chan School of Public HealthLaboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of OuluDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of MedicineDivision of Epidemiology, Department of Quantitative Health Sciences, Mayo ClinicDivision of Molecular Pathology, The Netherlands Cancer InstituteDepartment of Medical Epidemiology and Biostatistics, Karolinska InstitutetCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of MelbourneCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of MelbourneDepartment of Computational Biomedicine, Cedars-Sinai Medical CenterGenomics Center, Centre Hospitalier Universitaire de Québec – Université Laval Research CenterDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of CambridgeBiostatistics Unit, The Cyprus Institute of Neurology and GeneticsAbstract 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.https://doi.org/10.1186/s13058-024-01947-xPolygenic risk scoresBreast cancerRisk predictionRisk calibration
spellingShingle Kristia Yiangou
Nasim Mavaddat
Joe Dennis
Maria Zanti
Qin Wang
Manjeet K. Bolla
Mustapha Abubakar
Thomas U. Ahearn
Irene L. Andrulis
Hoda Anton-Culver
Natalia N. Antonenkova
Volker Arndt
Kristan J. Aronson
Annelie Augustinsson
Adinda Baten
Sabine Behrens
Marina Bermisheva
Amy Berrington de Gonzalez
Katarzyna Białkowska
Nicholas Boddicker
Clara Bodelon
Natalia V. Bogdanova
Stig E. Bojesen
Kristen D. Brantley
Hiltrud Brauch
Hermann Brenner
Nicola J. Camp
Federico Canzian
Jose E. Castelao
Melissa H. Cessna
Jenny Chang-Claude
Georgia Chenevix-Trench
Wendy K. Chung
NBCS Collaborators
Sarah V. Colonna
Fergus J. Couch
Angela Cox
Simon S. Cross
Kamila Czene
Mary B. Daly
Peter Devilee
Thilo Dörk
Alison M. Dunning
Diana M. Eccles
A. Heather Eliassen
Christoph Engel
Mikael Eriksson
D. Gareth Evans
Peter A. Fasching
Olivia Fletcher
Henrik Flyger
Lin Fritschi
Manuela Gago-Dominguez
Aleksandra Gentry-Maharaj
Anna González-Neira
Pascal Guénel
Eric Hahnen
Christopher A. Haiman
Ute Hamann
Jaana M. Hartikainen
Vikki Ho
James Hodge
Antoinette Hollestelle
Ellen Honisch
Maartje J. Hooning
Reiner Hoppe
John L. Hopper
Sacha Howell
Anthony Howell
ABCTB Investigators
kConFab Investigators
Simona Jakovchevska
Anna Jakubowska
Helena Jernström
Nichola Johnson
Rudolf Kaaks
Elza K. Khusnutdinova
Cari M. Kitahara
Stella Koutros
Vessela N. Kristensen
James V. Lacey
Diether Lambrechts
Flavio Lejbkowicz
Annika Lindblom
Michael Lush
Arto Mannermaa
Dimitrios Mavroudis
Usha Menon
Rachel A. Murphy
Heli Nevanlinna
Nadia Obi
Kenneth Offit
Tjoung-Won Park-Simon
Alpa V. Patel
Cheng Peng
Paolo Peterlongo
Guillermo Pita
Dijana Plaseska-Karanfilska
Katri Pylkäs
Paolo Radice
Muhammad U. Rashid
Gad Rennert
Eleanor Roberts
Juan Rodriguez
Atocha Romero
Efraim H. Rosenberg
Emmanouil Saloustros
Dale P. Sandler
Elinor J. Sawyer
Rita K. Schmutzler
Christopher G. Scott
Xiao-Ou Shu
Melissa C. Southey
Jennifer Stone
Jack A. Taylor
Lauren R. Teras
Irma van de Beek
Walter Willett
Robert Winqvist
Wei Zheng
Celine M. Vachon
Marjanka K. Schmidt
Per Hall
Robert J. MacInnis
Roger L. Milne
Paul D. P. Pharoah
Jacques Simard
Antonis C. Antoniou
Douglas F. Easton
Kyriaki Michailidou
Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction
Breast Cancer Research
Polygenic risk scores
Breast cancer
Risk prediction
Risk calibration
title Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction
title_full Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction
title_fullStr Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction
title_full_unstemmed Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction
title_short Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction
title_sort polygenic score distribution differences across european ancestry populations implications for breast cancer risk prediction
topic Polygenic risk scores
Breast cancer
Risk prediction
Risk calibration
url https://doi.org/10.1186/s13058-024-01947-x
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