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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk
M. Thomas, LC. Sakoda, M. Hoffmeister, EA. Rosenthal, JK. Lee, FJB. van Duijnhoven, EA. Platz, AH. Wu, CH. Dampier, A. de la Chapelle, A. Wolk, AD. Joshi, A. Burnett-Hartman, A. Gsur, A. Lindblom, A. Castells, AK. Win, B. Namjou, B. Van Guelpen,...
Language English Country United States
Document type Journal Article
Grant support
K07 CA188142
NCI NIH HHS - United States
T32 CA163177
NCI NIH HHS - United States
NV17-30920A
MZ0
CEP Register
Digital library NLK
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- MeSH
- Asian People genetics MeSH
- Bayes Theorem MeSH
- Genome-Wide Association Study MeSH
- Genetic Predisposition to Disease * MeSH
- Genome, Human genetics MeSH
- Risk Assessment * MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Colorectal Neoplasms epidemiology genetics pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Multifactorial Inheritance genetics MeSH
- Risk Factors MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
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
Biomedicine Institute University of León León 24071 Spain
Broad Institute of Harvard and MIT Cambridge MA 02141 USA
Cancer Epidemiology Division Cancer Council Victoria 615 St Kilda Road Melbourne VIC 3004 Australia
Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia PA 19104 USA
Center for Public Health Genomics University of Virginia Charlottesville VA 22903 USA
Centre for Public Health Research Massey University Wellington 6140 New Zealand
CIBER Epidemiología y Salud Pública Madrid 28029 Spain
Cincinnati VA Medical Center Cincinnati OH 45229 USA
Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN 37232 USA
Department of Biostatistics University of Washington Seattle WA 98195 USA
Department of Cardiovascular Medicine Mayo Clinic Rochester MN 55905 USA
Department of Clinical Genetics Karolinska University Hospital Stockholm 17177 Sweden
Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona 08907 Spain
Department of Epidemiology Harvard T H Chan School of Public Health Boston MA 02115 USA
Department of Epidemiology University of Washington Seattle WA 98195 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 University of Washington Medical Center Seattle WA 98195 USA
Department of Medicine Weill Cornell Medical College NY 10065 USA
Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm 17177 Sweden
Department of Oncologic Pathology Dana Farber Cancer Institute Boston MA 02215 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
Department of Surgery University of Virginia Health System Charlottesville VA 22903 USA
Departments of Pediatrics and Medicine Columbia University Medical Center New York NY 10032 USA
Division of Cancer Epidemiology German Cancer Research Center Heidelberg 69120 Germany
Division of Preventive Oncology German Cancer Research Center Heidelberg 69120 Germany
Division of Research Kaiser Permanente Northern California Oakland CA 94612 USA
Faculty of Medicine and Biomedical Center in Pilsen Charles University 323 00 Pilsen Czech Republic
Genome Sciences University of Washington Medical Center Seattle WA 98195 USA
Genomic Medicine and Family Cancer Clinic Royal Melbourne Hospital Parkville VIC 3010 Australia
German Cancer Consortium Heidelberg 69120 Germany
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
Memorial University of Newfoundland Discipline of Genetics St John's NL A1B 3R7 Canada
Office of Research and Development Department of Veterans Affairs Washington DC 20420 USA
Ontario Institute for Cancer Research Toronto ON M5G0A3 Canada
Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA 98109 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
School of Public Health University of Washington Seattle WA 98195 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 Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg 20246 Germany
University of Cincinnati College of Medicine Cincinnati OH 45229 USA
University of Hawaii Cancer Center Honolulu HI 96813 USA
University of Southern California Preventative Medicine Los Angeles CA 90089 USA
Wallenberg Centre for Molecular Medicine Umeå University Umeå 90187 Sweden
References provided by Crossref.org
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