Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

Int. J. Epidemiol. Advance Access published October 7, 2015 International Journal of Epidemiology, 2015, 1–20 doi: 10.1093/ije/dyv185 Original article Original article Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas Downloaded from http://ije.oxfordjournals.org/ at Serials RecordsSerials on October 14, 2015 Zahra Montazeri, 1† Evropi Theodoratou, 2† Christine Nyiraneza, 1 Maria Timofeeva, 3 Wanjing Chen, 2 Victoria Svinti, 3 Shanya Sivakumaran, 2 Gillian Gresham, 1 Laura Cubitt, 2 Luis Carvajal-Carmona, 4 Monica M. Bertagnolli, 5 Ann G. Zauber, 6 Ian Tomlinson, 7 Susan M. Farrington, 3 Malcolm G. Dunlop, 3 Harry Campbell 2,3 and Julian Little 1 * School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada, 2 Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK, 3 Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit Western General Hospital, Edinburgh, UK Biochemistry and Molecular Medicine, Genome and Biomedical Sciences Facility, UC Davis School of Medicine, University of California Davis, Davis, CA, USA, 5 Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA 6 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA and 7 Wellcome Trust Centre for Human Genetics, Oxford, UK *Corresponding author. School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Canada. E-mail: jlittle@uottawa.ca Joint first authors. Accepted 20 August 2015 Abstract Background: Low penetrance genetic variants, primarily single nucleotide polymorph- isms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database [http://www.chs.med.ed.ac.uk/CRAgene/]. Methods: We performed a systematic review, reviewing 9750 titles, and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations. Results: We considered the association with the rs6983267 variant at 8q24 as ‘highly cred- ible’, reaching genome-wide statistical significance in at least one meta-analysis model. We identified ‘less credible’ associations (higher heterogeneity, lower statistical power, BFDP u003e 0.02) with a further four variants of four independent genes: MTHFR c.677Cu003eT p.A222V C The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association V