BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.

Center for Cancer Research Medical University of Vienna Vienna Austria

Colorectal Cancer Group ONCOBELL Program Institut de Recerca Biomedica de Bellvitge L'Hospitalet de Llobregat Barcelona Spain

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

Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain

Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA

Department of Biostatistics University of Washington Seattle WA USA

Department of Clinical Sciences Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems L'Hospitalet de Llobregat Barcelona Spain

Department of Epidemiology University of Washington Seattle WA USA

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

Department of Pathology Microbiology and Immunology Vanderbilt University Medical Center Nashville TN USA

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

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

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

Division of Epidemiology Department of Medicine Vanderbilt Epidemiology Center Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville TN USA

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

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

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

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

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

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

Preventative Medicine University of Southern California Los Angeles CA USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA

University of Hawaii Cancer Center Honolulu HI USA

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

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