BACKGROUND: Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention. METHODS: We conducted genome-wide interaction analyses for 15 exposures with established or putative CRC risk [body mass index (BMI), height, physical activity, smoking, type 2 diabetes, use of menopausal hormone therapy, non-steroidal anti-inflammatory drugs, and intake of alcohol, calcium, fibre, folate, fruits, processed meat, red meat, and vegetables], and used interaction estimates to explore pathways and genes underlying CRC risk. The adaptive combination of Bayes Factors (ADABF), and over-representation analysis (ORA) were used for pathway analyses, and findings were further investigated using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)]. FINDINGS: A total of 1973 pathways using ADABF, and 840 pathways using ORA, out of the 2950 analysed, were enriched (P < 0.05) for at least one exposure, as well as 1227 genes within the enriched pathways. Data were available for 811/1227 coding genes in the OTP, 241 of which were supported by strong relative abundance of prior evidence (overall OTP score > 0.05). Fifty percent of the genes (617/1227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signalling hallmark. Our findings reflect previously established pathways for CRC risk and highlight the emerging importance of several less studied genes. Common pathways were found for several combinations of exposures, potentially suggesting common underlying mechanisms. INTERPRETATION: The results of the present analysis provide a basis for further functional research. If confirmed, they may help elucidate the etiological associations between risk factors and CRC risk and ultimately inform personalized prevention strategies. FUNDING: This study was funded by Cancer Research UK (CRUK; grant number:PPRCPJT∖100005) and World Cancer Research Fund International (WCRF; IIG_FULL_2020_022). Funding for grant IIG_FULL_2020_022 was obtained from Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme. Full funding details for the individual consortia are provided in the acknowledgements.

Broad Institute of Harvard and MIT Cambridge MA USA; Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA; Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA USA; Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia; Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne 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 NC USA

Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville VA USA; Department of Public Health Sciences Center for Public Health Genomics Charlottesville VA USA

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA USA; Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute 28029 Madrid Spain

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute 28029 Madrid Spain; Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona 08908 Spain

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Salt 17190 Girona Spain

Department of Computer Science Stanford University Stanford CA USA; Department of Genetics Stanford University Stanford CA USA

Department of Epidemiology and Biostatistics School of Public Health Faculty of Medicine Imperial College London London UK; Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Epidemiology and Biostatistics School of Public Health Faculty of Medicine Imperial College London London UK; Nutrition and Metabolism Branch International Agency for Research on Cancer Lyon France

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco CA USA

Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx NY USA

Department of Epidemiology Geisel School of Medicine at Dartmouth Hanover NH USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Family Medicine University of Virginia Charlottesville VA USA

Department of Health Research Methods Evidence and Impact McMaster University Hamilton ON Canada

Department of Mathematics Faculty of Natural Sciences Imperial College London London UK

Department of Medical Oncology and Therapeutics Research and Center for Precision Medicine City of Hope National Medical Center Duarte CA USA

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

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

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

Department of Population Science American Cancer Society Atlanta GA USA

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

Departments of Medicine and Epidemiology University of Pittsburgh Pittsburgh PA USA

Division of Biostatistics Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles CA USA

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

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany; School of Public Health Capital Medical University Beijing China

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

Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

Institute for Health Research Kaiser Permanente Colorado Denver CO USA

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Intermountain Health Salt Lake City UT USA

Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

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

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

Public Health Sciences Division Fred Hutchinson Cancer Center Seattle WA USA

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

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

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France

Slone Epidemiology Center at Boston University Boston MA USA

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