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

Zahra Montazeri, Evropi Theodoratou, Christine Nyiraneza, Maria Timofeeva, Wanjing Chen, Victoria Svinti, Shanya Sivakumaran, Gillian Gresham, Laura Cubitt, Luis Carvajal-Carmona, Monica M. Bertagnolli, Ann G. Zauber, Ian Tomlinson, Susan M. Farrington, Malcolm G. Dunlop, Harry Campbell, Julian Little

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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.

Original languageEnglish (US)
Pages (from-to)186-205
Number of pages20
JournalInternational Journal of Epidemiology
Volume45
Issue number1
DOIs
StatePublished - Feb 1 2016

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Genetic Association Studies
Adenoma
Meta-Analysis
Penetrance
Genes
Databases
Inborn Genetic Diseases
Single Nucleotide Polymorphism
Publications
Colorectal Neoplasms
Chronic Disease
Alleles
Genotype
Genome

ASJC Scopus subject areas

  • Epidemiology

Cite this

Montazeri, Z., Theodoratou, E., Nyiraneza, C., Timofeeva, M., Chen, W., Svinti, V., ... Little, J. (2016). Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas. International Journal of Epidemiology, 45(1), 186-205. https://doi.org/10.1093/ije/dyv185

Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas. / Montazeri, Zahra; Theodoratou, Evropi; Nyiraneza, Christine; Timofeeva, Maria; Chen, Wanjing; Svinti, Victoria; Sivakumaran, Shanya; Gresham, Gillian; Cubitt, Laura; Carvajal-Carmona, Luis; Bertagnolli, Monica M.; Zauber, Ann G.; Tomlinson, Ian; Farrington, Susan M.; Dunlop, Malcolm G.; Campbell, Harry; Little, Julian.

In: International Journal of Epidemiology, Vol. 45, No. 1, 01.02.2016, p. 186-205.

Research output: Contribution to journalArticle

Montazeri, Z, Theodoratou, E, Nyiraneza, C, Timofeeva, M, Chen, W, Svinti, V, Sivakumaran, S, Gresham, G, Cubitt, L, Carvajal-Carmona, L, Bertagnolli, MM, Zauber, AG, Tomlinson, I, Farrington, SM, Dunlop, MG, Campbell, H & Little, J 2016, 'Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas', International Journal of Epidemiology, vol. 45, no. 1, pp. 186-205. https://doi.org/10.1093/ije/dyv185
Montazeri, Zahra ; Theodoratou, Evropi ; Nyiraneza, Christine ; Timofeeva, Maria ; Chen, Wanjing ; Svinti, Victoria ; Sivakumaran, Shanya ; Gresham, Gillian ; Cubitt, Laura ; Carvajal-Carmona, Luis ; Bertagnolli, Monica M. ; Zauber, Ann G. ; Tomlinson, Ian ; Farrington, Susan M. ; Dunlop, Malcolm G. ; Campbell, Harry ; Little, Julian. / Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas. In: International Journal of Epidemiology. 2016 ; Vol. 45, No. 1. pp. 186-205.
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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.",
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AU - Chen, Wanjing

AU - Svinti, Victoria

AU - Sivakumaran, Shanya

AU - Gresham, Gillian

AU - Cubitt, Laura

AU - Carvajal-Carmona, Luis

AU - Bertagnolli, Monica M.

AU - Zauber, Ann G.

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