Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Stephanie A. Bien, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Yu Ru Su, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • David V. Conti, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Virginia Medical School
  • ,
  • Tabitha A. Harrison, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Conghui Qu, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Xingyi Guo, Vanderbilt Institute for Global Health (VIGH), University of Virginia Medical School
  • ,
  • Yingchang Lu, Vanderbilt Institute for Global Health (VIGH), University of Virginia Medical School
  • ,
  • Demetrius Albanes, National Cancer Institute, Bratislava, Slovakia, University of Virginia Medical School
  • ,
  • Paul L. Auer, University of Wisconsin-Milwaukee, University of Virginia Medical School
  • ,
  • Barbara L. Banbury, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Sonja I. Berndt, National Cancer Institute, Bratislava, Slovakia, University of Virginia Medical School
  • ,
  • Stéphane Bézieau, Centre Hospitalier Universitaire Hotel-Dieu, CHU Nantes, University of Virginia Medical School
  • ,
  • Hermann Brenner, German Cancer Research Center, Heidelberg, University of Virginia Medical School
  • ,
  • Daniel D. Buchanan, University Melbourne, Royal Melbourne Hospital, University of Virginia Medical School
  • ,
  • Bette J. Caan, Kaiser Permanente Medical Care Program of Northern California, University of Virginia Medical School
  • ,
  • Peter T. Campbell, American Cancer Society, University of Virginia Medical School
  • ,
  • Christopher S. Carlson, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Andrew T. Chan, Massachusetts General Hospital, Boston, Brigham and Women's Hospital, Boston, University of Virginia Medical School
  • ,
  • Jenny Chang-Claude, German Cancer Research Center, Heidelberg, University Medical Center Hamburg-Eppendorf, University of Virginia Medical School
  • ,
  • Sai Chen, University of Michigan School of Public Health, University of Virginia Medical School
  • ,
  • Charles M. Connolly, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Douglas F. Easton, Cambridge University, University of Virginia Medical School
  • ,
  • Edith J.M. Feskens, Wageningen University and Research Centre, University of Virginia Medical School
  • ,
  • Steven Gallinger, University of Toronto, University of Virginia Medical School
  • ,
  • Graham G. Giles, University Melbourne, Cancer Council Victoria, University of Virginia Medical School
  • ,
  • Marc J. Gunter
  • ,
  • Jochen Hampe, University Hospital Carl Gustav Carus, University of Virginia Medical School
  • ,
  • Jeroen R. Huyghe, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Michael Hoffmeister, German Cancer Research Center, Heidelberg, University of Virginia Medical School
  • ,
  • Thomas J. Hudson, Ontario Institute for Cancer Research, AbbVie, University of Virginia Medical School
  • ,
  • Eric J. Jacobs, American Cancer Society, University of Virginia Medical School
  • ,
  • Mark A. Jenkins, University Melbourne, University of Virginia Medical School
  • ,
  • Ellen Kampman, Wageningen University and Research Centre, University of Virginia Medical School
  • ,
  • Hyun Min Kang, University of Michigan School of Public Health, University of Virginia Medical School
  • ,
  • Tilman Kühn, German Cancer Research Center, Heidelberg, University of Virginia Medical School
  • ,
  • Sébastien Küry, Centre Hospitalier Universitaire Hotel-Dieu, CHU Nantes, University of Virginia Medical School
  • ,
  • Flavio Lejbkowicz, Clalit Health Services, Lady Davis Carmel Medical Center, University of Virginia Medical School
  • ,
  • Loic Le Marchand, University of Hawaii Manoa, University of Virginia Medical School
  • ,
  • Roger L. Milne, University Melbourne, Cancer Council Victoria, University of Virginia Medical School
  • ,
  • Li Li, Case Western Reserve University, University of Virginia Medical School
  • ,
  • Christopher I. Li, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Annika Lindblom, Karolinska University Hospital, Karolinska Institutet, University of Virginia Medical School
  • ,
  • Noralane M. Lindor, Mayo Clinic Scottsdale-Phoenix, Arizona, University of Virginia Medical School
  • ,
  • Vicente Martín, University of León, Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), University of Virginia Medical School
  • ,
  • Caroline E. McNeil, University of Southern California/Norris Comprehensive Cancer Center, University of Virginia Medical School
  • ,
  • Marilena Melas, University of Southern California/Norris Comprehensive Cancer Center, University of Virginia Medical School
  • ,
  • Victor Moreno, Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), L'Hospitalet de Llobregat, Universitat Pompeu Fabra, Barcelona, University of Virginia Medical School
  • ,
  • Polly A. Newcomb, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Kenneth Offit, Memorial Sloan Kettering Cancer Center, University of Virginia Medical School
  • ,
  • Paul D.P. Pharaoh, Cambridge University, University of Virginia Medical School
  • ,
  • John D. Potter, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Chenxu Qu, University of Southern California/Norris Comprehensive Cancer Center, University of Virginia Medical School
  • ,
  • Elio Riboli, Imperial College London, London, UK., University of Virginia Medical School
  • ,
  • Gad Rennert, Clalit Health Services, Lady Davis Carmel Medical Center, University of Virginia Medical School
  • ,
  • Núria Sala, Catalan Institute of Oncology-ICO, University of Virginia Medical School
  • ,
  • Clemens Schafmayer, University Hospital Schleswig-Holstein, University of Virginia Medical School
  • ,
  • Peter C. Scacheri, Case Western Reserve University, University of Virginia Medical School
  • ,
  • Stephanie L. Schmit, Moffitt Cancer Center, University of Virginia Medical School
  • ,
  • Gianluca Severi, Institut Gustave Roussy, University of Virginia Medical School
  • ,
  • Martha L. Slattery, University of Utah, University of Virginia Medical School
  • ,
  • Joshua D. Smith, University of Washington, Seattle, University of Virginia Medical School
  • ,
  • Antonia Trichopoulou, Hellenic Health Foundation, Athens, Medical Physics Laboratory, Medical School, University of Athens, Greece, University of Virginia Medical School
  • ,
  • Rosario Tumino, Affiliation Cancer Registry, Department of Prevention, Azienda Sanitaria Provinciale di Ragusa, University of Virginia Medical School
  • ,
  • Cornelia M. Ulrich, Huntsman Cancer Institute, University of Virginia Medical School
  • ,
  • Fränzel J.B. van Duijnhoven, Wageningen University and Research Centre, University of Virginia Medical School
  • ,
  • Bethany Van Guelpen, Clinical Sciences, Umea universitet, Klinisk vetenskap., University of Virginia Medical School
  • ,
  • Stephanie J. Weinstein, National Cancer Institute, Bratislava, Slovakia, University of Virginia Medical School
  • ,
  • Emily White, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Alicja Wolk, Karolinska Institutet, Uppsala universitet, University of Virginia Medical School
  • ,
  • Michael O. Woods, Memorial University of Newfoundland, University of Virginia Medical School
  • ,
  • Anna H. Wu, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Virginia Medical School
  • ,
  • Goncalo R. Abecasis, University of Michigan School of Public Health, University of Virginia Medical School
  • ,
  • Graham Casey, Institut Gustave Roussy, University of Virginia Medical School
  • ,
  • Deborah A. Nickerson, University of Washington, Seattle, University of Virginia Medical School
  • ,
  • Stephen B. Gruber, University of Southern California/Norris Comprehensive Cancer Center, University of Virginia Medical School
  • ,
  • Li Hsu, Fred Hutchinson Cancer Research Center, University of Virginia Medical School
  • ,
  • Wei Zheng, Vanderbilt Institute for Global Health (VIGH), University of Virginia Medical School, Vanderbilt University School of Medicine
  • ,
  • Ulrike Peters, Fred Hutchinson Cancer Research Center, University of Virginia Medical School

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.

OriginalsprogEngelsk
TidsskriftHuman Genetics
Vol/bind138
Nummer4
Sider (fra-til)307-326
Antal sider20
ISSN0340-6717
DOI
StatusUdgivet - 1 apr. 2019

Se relationer på Aarhus Universitet Citationsformater

ID: 155498666