Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta GA 30303 USA

Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia PA 19104 USA

Center for Autoimmune Genomics and Etiology Cincinnati Children's Hospital Medical Center Cincinnati OH 45229 USA; University of Cincinnati College of Medicine Cincinnati OH 45229 USA; Cincinnati VA Medical Center Cincinnati OH 45229 USA

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill NC 27599 USA

Center for Public Health Genomics University of Virginia Charlottesville VA 22903 USA

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne VIC 3000 Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne VIC 3000 Australia; Cancer Epidemiology Division Cancer Council Victoria 615 St Kilda Road Melbourne VIC 3004 Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne VIC 3000 Australia; Cancer Epidemiology Division Cancer Council Victoria 615 St Kilda Road Melbourne VIC 3004 Australia; Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VIC 3168 Australia

CIBER Epidemiología y Salud Pública University of León León 24071 Spain

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA; Department of Epidemiology Harvard T H Chan School of Public Health Boston MA 02115 USA

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA; Department of Epidemiology Harvard T H Chan School of Public Health Boston MA 02115 USA; Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA; Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA; Broad Institute of Harvard and MIT Cambridge MA 02141 USA; Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston MA 02115 USA

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA; Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA; Broad Institute of Harvard and MIT Cambridge MA 02141 USA; Department of Nutrition Harvard T H Chan School of Public Health Harvard University Boston MA 02115 USA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY 10021 USA; Department of Medicine Weill Cornell Medical College NY 10065 USA

Department of Bioinformatics and Medical Education University of Washington Medical Center Seattle WA 98195 USA

Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN 37232 USA

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center The Ohio State University Columbus OH 43210 USA

Department of Cardiovascular Medicine Mayo Clinic Rochester MN 55905 USA

Department of Clinical Genetics Karolinska University Hospital Stockholm 17177 Sweden; Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm 17177 Sweden

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA 02115 USA; Broad Institute of Harvard and MIT Cambridge MA 02141 USA; Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA; Department of Oncologic Pathology Dana Farber Cancer Institute Boston MA 02215 USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA 02115 USA; Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA; Department of Nutrition Harvard T H Chan School of Public Health Harvard University Boston MA 02108 USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21287 USA

Department of Family Medicine University of Virginia Charlottesville VA 22903 USA

Department of General Surgery University Hospital Rostock Rostock 18051 Germany

Department of Health Science Research Mayo Clinic Scottsdale AZ 85260 USA

Department of Health Sciences Research Mayo Clinic Rochester MN 55905 USA

Department of Internal Medicine University of Utah Salt Lake City UT 84132 USA

Department of Medicine 1 University Hospital Dresden Technische Universität Dresden Dresden 01062 Germany

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA 15219 USA

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA 90048 USA; Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles CA 90033 USA

Department of Medicine University of Washington Medical Center Seattle WA 98195 USA

Department of Medicine University of Washington Medical Center Seattle WA 98195 USA; Genome Sciences University of Washington Medical Center Seattle WA 98195 USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences 142 20 Prague 4 Czech Republic; Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University 128 00 Prague Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen Charles University 323 00 Pilsen Czech Republic

Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA 90089 USA

Department of Public Health and Primary Care University of Cambridge Cambridge CB2 0SR UK

Department of Radiation Sciences Oncology Unit Umeå University Umeå 90187 Sweden; Wallenberg Centre for Molecular Medicine Umeå University Umeå 90187 Sweden

Department of Surgery University of Virginia Health System Charlottesville VA 22903 USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Division of Cancer Epidemiology German Cancer Research Center Hamburg 20246 Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg 69120 Germany

Division of Epidemiology Department of Population Health New York University School of Medicine New York NY 10016 USA

Division of Human Genetics Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus OH 43210 USA

Division of Human Nutrition and Health Wageningen University and Research Wageningen 176700 the Netherlands

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN 85054 USA

Division of Research Kaiser Permanente Northern California Oakland CA 94612 USA

Gastroenterology Department Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona 08007 Spain

Huntsman Cancer Institute and Department of Population Health Sciences University of Utah Salt Lake City UT 84112 USA

Institute for Health Research Kaiser Permanente Colorado Denver CO 80014 USA

Institute of Cancer Research Department of Medicine 1 Medical University Vienna Vienna 1090 Austria

Institute of Environmental Medicine Karolinska Institutet Stockholm 17177 Sweden

Kaiser Permanente Washington Research Institute Seattle WA 98101 USA

Leeds Institute of Cancer and Pathology University of Leeds Leeds LS2 9JT UK

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto ON M5G1X5 Canada

Memorial University of Newfoundland Discipline of Genetics St John's NL A1B 3R7 Canada

Nutrition and Metabolism Section International Agency for Research on Cancer World Health Organization Lyon 69372 France

Office of Research and Development Department of Veterans Affairs Washington DC 20420 USA; Departments of Pediatrics and Medicine Columbia University Medical Center New York NY 10032 USA

Oncology Data Analytics Program Catalan Institute of Oncology L'Hospitalet de Llobregat Barcelona 08908 Spain; CIBER Epidemiología y Salud Pública L'Hospitalet de Llobregat Barcelona 08908 Spain

Ontario Institute for Cancer Research Toronto ON M5G0A3 Canada

PanCuRx Translational Research Initiative Ontario Institute for Cancer Research Toronto ON M5G0A3 Canada

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA; Centre for Public Health Research Massey University Wellington 6140 New Zealand

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA; Department of Biostatistics University of Washington Seattle WA 98195 USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA; Department of Epidemiology University of Washington Seattle WA 98195 USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA; Division of Research Kaiser Permanente Northern California Oakland CA 94612 USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 USA; School of Public Health University of Washington Seattle WA 98195 USA

School of Public Health Imperial College London London SW7 2AZ UK

School of Public Health Oregon Health and Science University Portland OR 97239 USA

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes 44093 France

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle WA 98109 USA

Translational Genomics Research Institute An Affiliate of City of Hope Phoenix AZ 85003 USA

University of Hawaii Cancer Center Honolulu HI 96813 USA

University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Parkville VIC 3010 Australia; Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville VIC 3010 Australia; Genomic Medicine and Family Cancer Clinic Royal Melbourne Hospital Parkville VIC 3010 Australia

University of Southern California Preventative Medicine Los Angeles CA 90089 USA

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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Response to Li and Hopper