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

doi:10.1093/ije/dyv185

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

Research output: Contribution to journal › Article › peer-review

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 language	English
Journal	International Journal of Epidemiology
DOIs	https://doi.org/10.1093/ije/dyv185
Publication status	Published - 7 Oct 2015

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Final-Polyp field synopsis- 17July15
This is a pre-copyedited, author-produced PDF of an article accepted for publication in International Journal of Epidemiology following peer review. The version of record for Montazeri Z, Theodoratou E, Nyiraneza C, Timofeeva M, Chen W, Svinti V et al. Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas. International Journal of Epidemiology. 2015 Oct 7. is available online at: http://ije.oxfordjournals.org/content/early/2015/10/07/ije.dyv185.short?rss=1
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Harry Campbell
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Genetic Epidemiology & Public Health
- Global Health Academy
- Usher Institute
- Centre for Global Health Research
Person: Academic: Research Active

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Montazeri, Z., Theodoratou, E., Nyiraneza, C., Timofeeva, M., Chen, W., Svinti, V., Sivakumaran, S., Gresham, G., Cubitt, L., Carvajal-Carmona, L., Bertagnolli, M. M., Zauber, A. G., Tomlinson, I., Farrington, S. M., Dunlop, M. G., Campbell, H., & Little, J. (2015). Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas. International Journal of Epidemiology. https://doi.org/10.1093/ije/dyv185

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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.",

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

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month = oct,

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doi = "10.1093/ije/dyv185",

language = "English",

journal = "International Journal of Epidemiology",

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publisher = "Oxford University Press",

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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 2015, 'Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas', International Journal of Epidemiology. https://doi.org/10.1093/ije/dyv185

TY - JOUR

T1 - Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

AU - Montazeri, Zahra

AU - Theodoratou, Evropi

AU - Nyiraneza, Christine

AU - Timofeeva, Maria

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

AU - Tomlinson, Ian

AU - Farrington, Susan M

AU - Dunlop, Malcolm G

AU - Campbell, Harry

AU - Little, Julian

PY - 2015/10/7

Y1 - 2015/10/7

N2 - 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.

AB - 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.

U2 - 10.1093/ije/dyv185

DO - 10.1093/ije/dyv185

M3 - Article

C2 - 26451011

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

ER -

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

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