UNLABELLED: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta Indonesia

BioRealm LLC Walnut California

Broad Institute of Harvard and MIT Cambridge Massachusetts

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Center for Cancer Research Medical University of Vienna Vienna Austria

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

Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville Virginia

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

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

Clalit National Cancer Control Center Haifa Israel

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

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 and Population Health Albert Einstein College of Medicine Bronx New York

Department of Epidemiology Geisel School of Medicine at Dartmouth Hanover New Hampshire

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 University of Washington School of Public Health 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 Medical Oncology and Therapeutics Research City of Hope National Medical Center Duarte California

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

Department of Medicine Boston University School of Medicine Slone Epidemiology Center Boston University Boston Massachusetts

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 Oncologic Pathology Dana Farber Cancer Institute Boston Massachusetts

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

Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles California

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

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Digestive Diseases and Microbiota Group Girona Biomedical Research Institute Salt Girona Spain

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 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

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

Genomic Medicine Institute Cleveland Clinic Cleveland Ohio

German Cancer Consortium Heidelberg Germany

Huntsman Cancer Institute Salt Lake City Utah

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

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

Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

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

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Denmark

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

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

Physical Activity Laboratory Baker Heart and Diabetes Institute Melbourne Australia

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 Harvard Medical School Boston Massachusetts

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

Research Centre for Hauora and Health Massey University Wellington New Zealand

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

School of Public Health Capital Medical University Beijing China

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington

Unit of Biomarkers and Susceptibility L'Hospitalet del 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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