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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.
Pubmed ID
30820706 (View this publication on the PubMed website)
Digital Object Identifier
Hum. Genet. 2019 Apr; Volume 138 (Issue 4): Pages 307-326
Bien SA, Su YR, Conti DV, Harrison TA, Qu C, Guo X, Lu Y, Albanes D, Auer PL, Banbury BL, Berndt SI, Bézieau S, Brenner H, Buchanan DD, Caan BJ, Campbell PT, Carlson CS, Chan AT, Chang-Claude J, Chen S, more Connolly CM, Easton DF, Feskens EJM, Gallinger S, Giles GG, Gunter MJ, Hampe J, Huyghe JR, Hoffmeister M, Hudson TJ, Jacobs EJ, Jenkins MA, Kampman E, Kang HM, Kühn T, Küry S, Lejbkowicz F, Le Marchand L, Milne RL, Li L, Li CI, Lindblom A, Lindor NM, Martín V, McNeil CE, Melas M, Moreno V, Newcomb PA, Offit K, Pharaoh PDP, Potter JD, Qu C, Riboli E, Rennert G, Sala N, Schafmayer C, Scacheri PC, Schmit SL, Severi G, Slattery ML, Smith JD, Trichopoulou A, Tumino R, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Abecasis GR, Casey G, Nickerson DA, Gruber SB, Hsu L, Zheng W, Peters U
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
  • Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
  • Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53205, USA.
  • Centre Hospitalier Universitaire Hotel-Dieu, 44093, Nantes, France.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA, 94612, USA. more
  • Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30329-4251, USA.
  • Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
  • Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Department of Public Health and Primary Care School of Clinical Medicine, University of Cambridge, Cambridge, England, 01223, UK.
  • Division of Human Nutrition, Wageningen University & Research, Wageningen, The Netherlands.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, 1X5, Canada.
  • Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
  • Medical Department 1, University Hospital Dresden, TU Dresden, 01307, Dresden, Germany.
  • Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Clalit Health Services National Israeli Cancer Control Center, 34361, Haifa, Israel.
  • University of Hawai'i Cancer Center, Honolulu, Hawaii, 96813, USA.
  • Department of Family Medicine and Community Health, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Department of Clinical Genetics, Karolinska University Hospital Solna, 171 77, Stockholm, Sweden.
  • Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
  • Biomedicine Institute (IBIOMED), University of León, León, Spain.
  • CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain.
  • Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB2 1TN, UK.
  • School of Public Health, Imperial College London, London, UK.
  • Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
  • Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24118, Kiel, Germany.
  • Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Inc, Tampa, FL, 33612, USA.
  • Centre for Research in Epidemiology and Population Health, Institut de Cancérologie Gustave Roussy, Villejuif, France.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • Department Genome Sciences, University of Washington, 98195, Seattle, WA, USA.
  • Hellenic Health Foundation, 13 Kaisareias & Alexandroupoleos, 115 27, Athens, Greece.
  • Affiliation Cancer Registry, Department of Prevention, Azienda Sanitaria Provinciale di Ragusa, Ragusa, Italy.
  • Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
  • Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
  • Institute of Environmental Medicine, Karolinska Institutet Solna, 17177, Stockholm, Sweden.
  • Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, Saint John's, NL, A1B 3V6, Canada.

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.

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