BACKGROUND: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. METHODS: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. RESULTS: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. CONCLUSIONS: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia

Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta Indonesia

BioRealm LLC Walnut California

Broad Institute of Harvard and MIT Cambridge Massachusetts

Broad Institute of MIT and Harvard Cambridge Massachusetts

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

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

Center for Public Health Genomics University of Virginia Charlottesville Virginia

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

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

CIBER Epidemiología y Salud Pública Madrid Spain

Clalit National Cancer Control Center Haifa Israel

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

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville Victoria Australia

Computer Science Department School of Computer Science Bina Nusantara University Jakarta Indonesia

Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain

Department of Biostatistics University of Washington Seattle Washington

Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Computer Science Stanford University Stanford California

Department of Epidemiology and Biostatistics Imperial College London School of Public Health London United Kingdom

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston Massachusetts

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland

Department of Epidemiology Richard M Fairbanks School of Public Health Indianapolis Indiana

Department of Epidemiology School of Public Health University of Washington Seattle Washington

Department of Family Medicine University of Virginia Charlottesville Virginia

Department of Genetics and Genome Sciences Case Western Reserve University Cleveland Ohio

Department of Genetics Stanford University Stanford California

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston Massachusetts

Department of Internal Medicine University of Utah Salt Lake City Utah

Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale Arizona

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh Pennsylvania

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles California

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Nutritional Sciences University of Michigan School of Public Health Ann Arbor Michigan

Department of Pathology School of Medicine Umm Al Qura'a University Saudi Arabia

Department of Population Health Sciences University of Utah Salt Lake City Utah

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

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

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Division of Biostatistics Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles California

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda Maryland

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

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

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts

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

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

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Research Kaiser Permanente Northern California Oakland California

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Genetic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville Victoria Australia

Genomic Medicine Institute Cleveland Clinic Cleveland Ohio

German Cancer Consortium Heidelberg Germany

Harvard Medical School Boston Massachusetts

Huntsman Cancer Institute Salt Lake City Utah

Huntsman Cancer Institute University of Utah Salt Lake City Utah

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

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

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

IU Melvin and Bren Simon Cancer Center Indiana University Indianapolis Indiana

Leeds Institute of Cancer and Pathology University of Leeds Leeds United Kingdom

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada

Memorial University of Newfoundland Discipline of Genetics St John's Canada

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

ONCOBEL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Oncology Data Analytics Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain

Population and Cancer Prevention Program Case Comprehensive Cancer Center Cleveland Ohio

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

Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital Boston Massachusetts

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

School of Public Health Capital Medical University Beijing China

Section of Nutrition and Metabolism International Agency for Research on Cancer Lyon France

Slone Epidemiology Center at Boston University Boston Massachusetts

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington

Unit of Nutrition Environment and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology Avda Gran Via Barcelona 199 203 08908L'Hospitalet de Llobregat Barcelona Spain

University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

University of Hawaii Cancer Center Honolulu Hawaii

University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Parkville Victoria Australia

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

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