BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia

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 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

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

Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor Michigan

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

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa Florida

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

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel; Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

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

Department of Family Medicine University of Virginia Charlottesville Virginia

Department of General Surgery University Hospital Rostock Rostock Germany

Department of Genome Sciences University of Washington Seattle Washington

Department of Hematology Oncology Chonnam National University Hospital Hwasun South Korea

Department of Internal Medicine University of Utah Salt Lake City Utah

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

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

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

Department of Population and Quantitative Health Sciences Case Western Reserve University Cleveland Ohio

Department of Preventive Medicine and University of Southern California Norris Comprehensive Cancer Center 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

Department of Surgery Chonnam National University Hwasun Hospital and Medical School Hwasun Korea

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; University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

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

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany; Division of Preventive Oncology German Cancer Research Center and National Center for Tumor Diseases Heidelberg Germany

Division of Epidemiology Department of Medicine Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville Tennessee

Division of Epidemiology Department of Population Health New York University School of Medicine New York New York

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Channing Division of Network Medicine Brigham and Women's 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 Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington

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

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington; Division of Research Kaiser Permanente Northern California Oakland California

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington; School of Public Health University of Washington Seattle Washington

Gastroenterology Department Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas University of Barcelona Barcelona Spain

Health Sciences Research Mayo Clinic Scottsdale Arizona

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

Institute for Health Research Kaiser Permanente Colorado Denver Colorado

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

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

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 Newfoundland and Labrador Canada

National University Cancer Institute Singapore; Cancer Science Institute of Singapore National University of Singapore Singapore

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

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

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes France

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington

The Kidney Disease Center the 1st Affiliated Hospital Institute of Translational Medicine Zhejiang University School of Medicine Hangzhou China

University of Hawaii Cancer Center Honolulu Hawaii

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Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries