Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

'Agii Anargiri' Cancer Hospital Athens Greece

Aalborg University Department of Clinical Medicine Aalborg Denmark

Aalborg University Hospital Clinical Cancer Research Center Aalborg Denmark

Aalborg University Hospital Molecular Diagnostics Aalborg Denmark

Aichi Cancer Center Research Institute Division of Cancer Epidemiology and Prevention Nagoya Japan

Alberta Health Services Department of Cancer Epidemiology and Prevention Research Calgary AB Canada

Bashkir State University Department of Genetics and Fundamental Medicine Ufa Russia

BC Cancer Cancer Control Research Vancouver BC Canada

BC Cancer Research Centre Department of Molecular Oncology Vancouver BC Canada

BC Cancer Vancouver General Hospital and University of British Columbia British Columbia's Ovarian Cancer Research Program Vancouver BC Canada

Beckman Research Institute of City of Hope Department of Population Sciences Duarte CA USA

Beth Israel Deaconess Medical Center Department of Medical Oncology Boston MA USA

Biomedical Network on Rare Diseases Madrid Spain

Brigham and Women's Hospital and Harvard Medical School Channing Division of Network Medicine Boston MA USA

Brigham and Women's Hospital and Harvard Medical School Obstetrics and Gynecology Epidemiology Center Boston MA USA

Cambridge Cambridge UK

Cancer Council Victoria Cancer Epidemiology Division Melbourne VIC Australia

Cancer Genetics Centre Hong Kong Hereditary Breast Cancer Family Registry Happy Valley Hong Kong

Cancer Research Malaysia Breast Cancer Research Programme Subang Jaya Selangor Malaysia

Cancer Research UK Cambridge Institute University of Cambridge Cambridge UK

Cedars Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute Cancer Prevention and Genetics Program Los Angeles CA USA

Center for Bioinformatics and Functional Genomics Cedars Sinai Medical Center Los Angeles CA USA

Centre Hospitalier Universitaire de Québec Université Laval Research Center Genomic Center Québec City QC Canada

Centre Hospitalier Universitaire de Québec Université Laval Research Center Genomics Center Québec City QC Canada

Centro de Investigación en Red de Enfermedades Raras Madrid Spain

Chaim Sheba Medical Center The Susanne Levy Gertner Oncogenetics Unit Ramat Gan Israel

CIBERONC Hospital Clinico San Carlos IdISSC Molecular Oncology Laboratory Madrid Spain

City of Hope Clinical Cancer Genetics Community Research Network Duarte CA USA

City of Hope Clinical Cancer Genomics Duarte CA USA

Columbia University Department of Epidemiology Mailman School of Public Health New York NY USA

Columbia University Departments of Pediatrics and Medicine New York NY USA

Dana Farber Cancer Institute Cancer Risk and Prevention Clinic Boston MA USA

Danish Cancer Society Research Center Department of Virus Lifestyle and Genes Copenhagen Denmark

Dartmouth College Geisel School of Medicine Hanover NH USA

Division of Human Genetics The Ohio State University Department of Internal Medicine Columbus OH USA

Dr Horst Schmidt Kliniken Wiesbaden Department of Gynecology and Gynecologic Oncology Wiesbaden Germany

Duke Cancer Institute Cancer Control and Population Sciences Durham NC USA

Duke University Hospital Department of Community and Family Medicine Durham NC USA

Duke University Hospital Department of Gynecologic Oncology Durham NC USA

Duke University Hospital Department of Surgery Durham NC USA

Emory University Department of Epidemiology Rollins School of Public Health Atlanta GA USA

Ev Kliniken Essen Mitte Department of Gynecology and Gynecologic Oncology Essen Germany

Faculty of Medicine and University Hospital Cologne University of Cologne Center for Familial Breast and Ovarian Cancer Cologne Germany

Faculty of Medicine and University Hospital Cologne University of Cologne Center for Integrated Oncology Cologne Germany

Faculty of Medicine and University Hospital Cologne University of Cologne Center for Molecular Medicine Cologne Cologne Germany

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Unit of Medical Genetics Department of Medical Oncology and Hematology Milan Italy

Fondazione IRCCS Istituto Nazionale dei Tumori Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Milan Italy

Fox Chase Cancer Center Department of Clinical Genetics Philadelphia PA USA

Fox Chase Cancer Center Population Studies Facility Philadelphia PA USA

Fred Hutchinson Cancer Research Center Program in Epidemiology Division of Public Health Sciences Seattle WA USA

Fred Hutchinson Cancer Research Center Seattle WA USA

Fundación Pública Galega de Medicina Xenómica Santiago de Compostela Spain

Fundación Pública Galega Medicina Xenómica Santiago De Compostela Spain

Genome Institute of Singapore Human Genetics Division Singapore Singapore

German Cancer Research Center Division of Cancer Epidemiology Heidelberg Germany

German Cancer Research Center Molecular Genetics of Breast Cancer Heidelberg Germany

Ghent University Centre for Medical Genetics Gent Belgium

Hannover Medical School Department of Radiation Oncology Hannover Germany

Hannover Medical School Gynaecology Research Unit Hannover Germany

Harvard T H Chan School of Public Health Department of Epidemiology Boston MA USA

Haukeland University Hospital Department of Obstetrics and Gynecology Bergen Norway

Hebei Medical University 4th Hospital Department of Molecular Biology Shijiazhuang China

Hebei Medical University 4th Hospital Department of Obstetrics and Gynaecology Shijiazhuang China

Hong Kong Sanatorium and Hospital Department of Surgery Happy Valley Hong Kong

Humboldt Universität zu Berlin and Berlin Institute of Health Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow Klinikum Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Berlin Germany

Huntsman Cancer Institute Department of Medicine Salt Lake City UT USA

Icahn School of Medicine at Mount Sinai Department of Genetics and Genomic Sciences New York NY USA

Icahn School of Medicine at Mount Sinai Department of Population Health Science and Policy New York NY USA

IEO European Institute of Oncology IRCCS Division of Cancer Prevention and Genetics Milan Italy

IFOM the FIRC Institute of Molecular Oncology Genome Diagnostics Program Milan Italy

Imperial College London Division of Cancer and Ovarian Cancer Action Research Centre Department of Surgery and Cancer London UK

Imperial College London Division of Cancer and Ovarian Cancer Action Research Centre Department Surgery and Cancer London UK

INSERM U830 Department of Tumour Biology Paris France

Inserm U900 Genetic Epidemiology of Cancer team Paris France

Institut Curie Paris France

Institut Curie Service de Génétique Paris France

Institute of Biochemistry and Experimental Oncology 1st Faculty od Medicine Charles University Prague Czech Republic

Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain

Instituto de Investigación Sanitaria de Santiago de Compostela Santiago De Compostela Spain

Jena University Hospital Friedrich Schiller University Department of Gynaecology Jena Germany

Jonsson Comprehensive Cancer Centre UCLA Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Los Angeles CA USA

Karolinska Institutet Clinical Genetics Stockholm Sweden

Karolinska Institutet Institute of Environmental Medicine Stockholm Sweden

Landspitali University Hospital Department of Oncology Reykjavik Iceland

Landspitali University Hospital Department of Pathology Reykjavik Iceland

Latvian Biomedical Research and Study Centre Riga Latvia

Leiden University Medical Center Department of Human Genetics Leiden The Netherlands

Leiden University Medical Center Department of Pathology Leiden The Netherlands

Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Lund University and Skåne University Hospital Department of Oncology Lund Sweden

Lund University Department of Cancer Epidemiology Clinical Sciences Lund Sweden

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Fred A Litwin Center for Cancer Genetics Toronto ON Canada

Magee Womens Hospital University of Pittsburgh School of Medicine Department of Medicine Pittsburgh PA USA

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA

Magee Womens Research Institute and Hillman Cancer Center Womens Cancer Research Center Pittsburgh PA USA

Maria Sklodowska Curie National Research Institute of Oncology Department of Pathology and Laboratory Diagnostics Warsaw Poland

Masaryk Memorial Cancer Institute Department of Cancer Epidemiology and Genetics Brno Czech Republic

Mayo Clinic Department of Health Science Research Division of Epidemiology Rochester MN USA

Mayo Clinic Department of Health Sciences Research Division of Biomedical Statistics and Informatics Rochester MN USA

Mayo Clinic Department of Laboratory Medicine and Pathology Rochester MN USA

McGill University Program in Cancer Genetics Departments of Human Genetics and Oncology Montréal QC Canada

Medical University of South Carolina Hollings Cancer Center Charleston SC USA

Medical University of Vienna Dept of OB GYN and Comprehensive Cancer Center Vienna Austria

Memorial Sloan Kettering Cancer Center Clinical Genetics Research Lab Department of Cancer Biology and Genetics New York NY USA

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Memorial Sloan Kettering Cancer Center Gynecology Service Department of Surgery New York NY USA

Mines ParisTech Fontainebleau France

Moffitt Cancer Center Department of Cancer Epidemiology Tampa FL USA

Monash University Precision Medicine School of Clinical Sciences at Monash Health Clayton VIC Australia

N N Alexandrov Research Institute of Oncology and Medical Radiology Minsk Belarus

N N Petrov Institute of Oncology St Petersburg Russia

Nagoya University Graduate School of Medicine Division of Cancer Epidemiology Nagoya Japan

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National Cancer Centre Cancer Genetics Service Singapore Singapore

National Cancer Institute Clinical Genetics Branch Division of Cancer Epidemiology and Genetics Bethesda MD USA

National Cancer Institute Division of Cancer Epidemiology and Genetics Bethesda MD USA

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National Centre for Scientific Research 'Demokritos' Molecular Diagnostics Laboratory INRASTES Athens Greece

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Netherlands Comprehensive Cancer Organisation Utrecht The Netherlands

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Pomeranian Medical University Department of Genetics and Pathology Szczecin Poland

Pomeranian Medical University Independent Laboratory of Molecular Biology and Genetic Diagnostics Szczecin Poland

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Portuguese Oncology Institute Department of Genetics Porto Portugal

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Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen The Netherlands

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Roswell Park Cancer Institute Cancer Pathology and Prevention Division of Cancer Prevention and Population Sciences Buffalo NY USA

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Roswell Park Cancer Institute Division of Cancer Prevention and Control Buffalo NY USA

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Royal Alexandra Hospital Department of Obstetrics and Gynecology Division of Gynecologic Oncology Edmonton AB Canada

Royal Pass Road Tampa FL USA

Rutgers Cancer Institute of New Jersey Cancer Prevention and Control Program New Brunswick NJ USA

Saint Petersburg State University Saint Petersburg Russia

Samuel Lunenfeld Research Institute Public Health Ontario Toronto ON Canada

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Seoul National University College of Medicine Department of Preventive Medicine Seoul Korea

Seoul National University Graduate School Department of Biomedical Sciences Seoul Korea

Spanish National Cancer Research Centre Human Cancer Genetics Programme Madrid Spain

St Mary's Hospital Manchester University NHS Foundation Trust Manchester Academic Health Science Centre North West Genomics Laboratory Hub Manchester Centre for Genomic Medicine Manchester UK

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State Research Institute Centre for Innovative Medicine Vilnius Lithuania

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Tel Aviv University Sackler Faculty of Medicine Ramat Aviv Israel

The Institute of Cancer Research Division of Breast Cancer Research London UK

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The Netherlands Cancer Institute Antoni van Leeuwenhoek hospital Family Cancer Clinic Amsterdam The Netherlands

The Ohio State University Department of Cancer Biology and Genetics Columbus OH USA

The University of Chicago Center for Clinical Cancer Genetics Chicago IL USA

The University of Chicago Pritzker School of Medicine Chicago IL USA

The University of Hong Kong Department of Surgery Pok Fu Lam Hong Kong

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Tianjin Medical University Cancer Institute and Hospital Department of Epidemiology Tianjin China

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Ufa Federal Research Centre of the Russian Academy of Sciences Institute of Biochemistry and Genetics Ufa Russia

Université Paris Descartes Paris France

University College London MRC Clinical Trials Unit at UCL Institute of Clinical Trials and Methodology London UK

University Hospital Erlangen Friedrich Alexander University Erlangen Nuremberg Department of Gynecology and Obstetrics Comprehensive Cancer Center ER EMN Erlangen Germany

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University Hospital SOD Genetica Molecolare Pisa Italy

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University Hospitals Leuven Division of Gynecologic Oncology Department of Obstetrics and Gynaecology and Leuven Cancer Institute Leuven Belgium

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University of Bergen Centre for Cancer Biomarkers CCBIO Department of Clinical Science Bergen Norway

University of British Columbia Department of Obstetrics and Gynecology Vancouver BC Canada

University of British Columbia Department of Pathology and Laboratory Medicine Vancouver BC Canada

University of California at Los Angeles David Geffen School of Medicine Department of Medicine Division of Hematology and Oncology Los Angeles CA USA

University of California at Los Angeles David Geffen School of Medicine Department of Obstetrics and Gynecology Los Angeles CA USA

University of California Irvine Department of Epidemiology Genetic Epidemiology Research Institute Irvine CA USA

University of Cambridge Centre for Cancer Genetic Epidemiology Department of Oncology Cambridge UK

University of Cambridge Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Cambridge UK

University of Cambridge Department of Medical Genetics Cambridge UK

University of Cambridge Department of Public Health and Primary Care Cambridge UK

University of Copenhagen Department of Gynaecology Rigshospitalet Copenhagen Denmark

University of Copenhagen Molecular Unit Department of Pathology Herlev Hospital Copenhagen Denmark

University of Florence Department of Experimental and Clinical Biomedical Sciences 'Mario Serio' Medical Genetics Unit Florence Italy

University of Glasgow Institute of Cancer Sciences Glasgow UK

University of Hawaii Cancer Center Cancer Epidemiology Program Honolulu HI USA

University of Helsinki Department of Obstetrics and Gynecology Helsinki University Hospital Helsinki Finland

University of Helsinki Department of Pathology Helsinki University Hospital Helsinki Finland

University of Iceland BMC Faculty of Medicine Reykjavik Iceland

University of Kansas Medical Center Department of Pathology and Laboratory Medicine Kansas City KS USA

University of Leipzig Institute for Medical Informatics Statistics and Epidemiology Leipzig Germany

University of Leipzig LIFE Leipzig Research Centre for Civilization Diseases Leipzig Germany

University of Leuven Laboratory for Translational Genetics Department of Human Genetics Leuven Belgium

University of Malaya Department of Obstetrics and Gynaecology University of Malaya Medical Centre Kuala Lumpur Malaysia

University of Malaya Department of Surgery Faculty of Medicine Kuala Lumpur Malaysia

University of Manchester Manchester Academic Health Science Centre Division of Evolution and Genomic Sciences School of Biological Sciences Faculty of Biology Medicine and Health Manchester UK

University of Michigan School of Public Health Department of Epidemiology Ann Arbor MI USA

University of New Mexico University of New Mexico Health Sciences Center Albuquerque NM USA

University of NSW Sydney Adult Cancer Program Lowy Cancer Research Centre Sydney NSW Australia

University of NSW Sydney School of Women's and Children's Health Faculty of Medicine Sydney NSW Australia

University of Oxford Cancer Epidemiology Unit Oxford UK

University of Pennsylvania Basser Center for BRCA Abramson Cancer Center Philadelphia PA USA

University of Pittsburgh School of Medicine Division of Gynecologic Oncology Department of Obstetrics Gynecology and Reproductive Sciences Pittsburgh PA USA

University of Porto Biomedical Sciences Institute Porto Portugal

University of Pretoria Department of Genetics Arcadia South Africa

University of South Florida Epidemiology Center College of Medicine Tampa FL USA

University of Southampton Faculty of Medicine Southampton UK

University of Southern California Department of Preventive Medicine Keck School of Medicine Los Angeles CA USA

University of Southern California Norris Comprehensive Cancer Center Department of Preventive Medicine Keck School of Medicine Los Angeles CA USA

University of Texas MD Anderson Cancer Center Department of Breast Medical Oncology Houston TX USA

University of Texas MD Anderson Cancer Center Department of Epidemiology Houston TX USA

University of Texas MD Anderson Cancer Center Department of Gynecologic Oncology and Clinical Cancer Genetics Program Houston TX USA

University of Toronto Department of Molecular Genetics Toronto ON Canada

University of Utah Huntsman Cancer Institute Department of Population Health Sciences Salt Lake City UT USA

University of Washington Department of Epidemiology Seattle WA USA

Uppsala University Department of Surgical Sciences Uppsala Sweden

Vall d'Hebron Institute of Oncology Hereditary cancer Genetics Group Barcelona Spain

Vall dHebron Institute of Oncology Oncogenetics Group Barcelona Spain

Vanderbilt University Medical Center Division of Quantitative Sciences Department of Obstetrics and Gynecology Department of Biomedical Sciences Women's Health Research Nashville TN USA

Vanderbilt University School of Medicine Division of Epidemiology Department of Medicine Vanderbilt Epidemiology Center Vanderbilt Ingram Cancer Center Nashville TN USA

Veneto Institute of Oncology IOV IRCCS Immunology and Molecular Oncology Unit Padua Italy

VIB Center for Cancer Biology Leuven Belgium

Vilnius University Hospital Santariskiu Clinics Hematology oncology and transfusion medicine center Dept of Molecular and Regenerative Medicine Vilnius Lithuania

Westmead Hospital Department of Gynaecological Oncology Sydney NSW Australia

Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Centre Department of Obstetrics and Gynecology Los Angeles CA USA

Yale School of Public Health Chronic Disease Epidemiology New Haven CT USA

Erratum v

Eur J Hum Genet. 2022 May;30(5):630-631. doi: 10.1038/s41431-022-01085-y. PubMed

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Welcome to CanRisk. [cited 2021 Aug 15]. https://canrisk.org/

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GA4GH Phenopacket-Driven Characterization of Genotype-Phenotype Correlations in Mendelian Disorders

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Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?