title: Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas.
abstract: BACKGROUND
  Low penetrance genetic variants, primarily single nucleotide polymorphisms, 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 credible', reaching genome-wide statistical significance in at least one meta-analysis model. We identified 'less credible' associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations.
  
  
  CONCLUSIONS
  The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRA gene database provides context for CRA genetic association data and will help inform future research directions.
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Montazeri
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Evropi
authors.initials: E
authors.lastname: Theodoratou
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Nyiraneza
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Timofeeva
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Wanjing
authors.initials: W
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Victoria
authors.initials: V
authors.lastname: Svinti
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Shanya
authors.initials: S
authors.lastname: Sivakumaran
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Gillian
authors.initials: G
authors.lastname: Gresham
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Cubitt
authors.affiliation: Biochemistry and Molecular Medicine, Genome and Biomedical Sciences Facility, UC Davis School of Medicine, University of California Davis, Davis, CA, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Carvajal-Carmona
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA and.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Zauber
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: 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.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Farrington
authors.affiliation: 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.
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK, 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.
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada, jlittle@uottawa.ca.
authors.forename: Julian
authors.initials: J
authors.lastname: Little
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001499:Bayes Theorem; D015179:Colorectal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D007527:Isoenzymes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1