Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Nikos Papadimitriou; Caroline J Bull; Mazda Jenab; David J Hughes; Joshua A Bell; Eleanor Sanderson; Nicholas J Timpson; George Davey Smith; Demetrius Albanes; Peter T Campbell; Sébastien Küry; Loic Le Marchand; Cornelia M Ulrich; Kala Visvanathan; Jane C Figueiredo; Polly A Newcomb; Rish K Pai; Ulrike Peters; Kostas K Tsilidis; Jolanda M A Boer; Emma E Vincent; Daniela Mariosa; Marc J Gunter; Tom G Richardson; Neil Murphy

doi:10.1186/s12916-022-02702-9

Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Nikos Papadimitriou^*, Caroline J Bull, Mazda Jenab, David J Hughes, Joshua A Bell, Eleanor Sanderson, Nicholas J Timpson, George Davey Smith, Demetrius Albanes, Peter T Campbell, Sébastien Küry, Loic Le Marchand, Cornelia M Ulrich, Kala Visvanathan, Jane C Figueiredo, Polly A Newcomb, Rish K Pai, Ulrike Peters, Kostas K Tsilidis, Jolanda M A BoerEmma E Vincent, Daniela Mariosa, Marc J Gunter, Tom G Richardson, Neil Murphy

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.

METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.

RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).

CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

Original language	English
Article number	5
Pages (from-to)	5
Journal	BMC Medicine
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12916-022-02702-9
Publication status	Published - 4 Jan 2023

Bibliographical note

Funding Information:
J.A.B. works in a unit funded by the UK MRC (MC_UU_00011/1) and the University of Bristol.

Funding Information:
NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011) and the MRC Integrative Epidemiology Unit (MC_UU_12013/3), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169).

Funding Information:
Information on consortia acknowledgements is included in the Additional file 2 : Acknowledgements. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.

Funding Information:
C.J.B. is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009).

Funding Information:
KKT is supported by Cancer Research UK (PPRCPJT\100005)

Funding Information:
E.E.V. is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019).

Funding Information:
This work was supported by Cancer Research UK (C18281/A29019)

Publisher Copyright:
© 2022, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Groups and Themes

Bristol Population Health Science Institute

Keywords

Adult
Humans
Child
Middle Aged
Adiposity/genetics
Pediatric Obesity
Risk Factors
Mendelian Randomization Analysis
Genome-Wide Association Study
Body Mass Index
Colonic Neoplasms
Polymorphism, Single Nucleotide

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10.1186/s12916-022-02702-9Licence: CC BY

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research
IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

Papadimitriou, N., Bull, C. J., Jenab, M., Hughes, D. J., Bell, J. A., Sanderson, E., Timpson, N. J., Smith, G. D., Albanes, D., Campbell, P. T., Küry, S., Le Marchand, L., Ulrich, C. M., Visvanathan, K., Figueiredo, J. C., Newcomb, P. A., Pai, R. K., Peters, U., Tsilidis, K. K., ... Murphy, N. (2023). Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study. BMC Medicine, 21(1), 5. Article 5. https://doi.org/10.1186/s12916-022-02702-9

@article{59ffbbaafd9548a691d2be455fa923bb,

title = "Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study",

abstract = "BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95\% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95\% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95\% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95\% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95\% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95\% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95\% CI: 1.03, 1.57), colon (OR: 1.32, 95\% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95\% CI: 1.21, 2.05).CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.",

keywords = "Adult, Humans, Child, Middle Aged, Adiposity/genetics, Pediatric Obesity, Risk Factors, Mendelian Randomization Analysis, Genome-Wide Association Study, Body Mass Index, Colonic Neoplasms, Polymorphism, Single Nucleotide",

author = "Nikos Papadimitriou and Bull, \{Caroline J\} and Mazda Jenab and Hughes, \{David J\} and Bell, \{Joshua A\} and Eleanor Sanderson and Timpson, \{Nicholas J\} and Smith, \{George Davey\} and Demetrius Albanes and Campbell, \{Peter T\} and S{\'e}bastien K{\"u}ry and \{Le Marchand\}, Loic and Ulrich, \{Cornelia M\} and Kala Visvanathan and Figueiredo, \{Jane C\} and Newcomb, \{Polly A\} and Pai, \{Rish K\} and Ulrike Peters and Tsilidis, \{Kostas K\} and Boer, \{Jolanda M A\} and Vincent, \{Emma E\} and Daniela Mariosa and Gunter, \{Marc J\} and Richardson, \{Tom G\} and Neil Murphy",

note = "Funding Information: J.A.B. works in a unit funded by the UK MRC (MC\_UU\_00011/1) and the University of Bristol. Funding Information: NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC \& WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011) and the MRC Integrative Epidemiology Unit (MC\_UU\_12013/3), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Funding Information: Information on consortia acknowledgements is included in the Additional file 2 : Acknowledgements. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: C.J.B. is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG\_2019\_2009). Funding Information: KKT is supported by Cancer Research UK (PPRCPJT\textbackslash{}100005) Funding Information: E.E.V. is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG\_2019\_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Funding Information: This work was supported by Cancer Research UK (C18281/A29019) Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = jan,

day = "4",

doi = "10.1186/s12916-022-02702-9",

language = "English",

volume = "21",

pages = "5",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central Ltd",

number = "1",

}

Papadimitriou, N, Bull, CJ, Jenab, M, Hughes, DJ, Bell, JA, Sanderson, E , Timpson, NJ , Smith, GD, Albanes, D, Campbell, PT, Küry, S, Le Marchand, L, Ulrich, CM, Visvanathan, K, Figueiredo, JC, Newcomb, PA, Pai, RK, Peters, U, Tsilidis, KK, Boer, JMA, Vincent, EE, Mariosa, D, Gunter, MJ, Richardson, TG & Murphy, N 2023, 'Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study', BMC Medicine, vol. 21, no. 1, 5, pp. 5. https://doi.org/10.1186/s12916-022-02702-9

TY - JOUR

T1 - Separating the effects of early and later life adiposity on colorectal cancer risk

T2 - a Mendelian randomization study

AU - Papadimitriou, Nikos

AU - Bull, Caroline J

AU - Jenab, Mazda

AU - Hughes, David J

AU - Bell, Joshua A

AU - Sanderson, Eleanor

AU - Timpson, Nicholas J

AU - Smith, George Davey

AU - Albanes, Demetrius

AU - Campbell, Peter T

AU - Küry, Sébastien

AU - Le Marchand, Loic

AU - Ulrich, Cornelia M

AU - Visvanathan, Kala

AU - Figueiredo, Jane C

AU - Newcomb, Polly A

AU - Pai, Rish K

AU - Peters, Ulrike

AU - Tsilidis, Kostas K

AU - Boer, Jolanda M A

AU - Vincent, Emma E

AU - Mariosa, Daniela

AU - Gunter, Marc J

AU - Richardson, Tom G

AU - Murphy, Neil

N1 - Funding Information: J.A.B. works in a unit funded by the UK MRC (MC_UU_00011/1) and the University of Bristol. Funding Information: NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011) and the MRC Integrative Epidemiology Unit (MC_UU_12013/3), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Funding Information: Information on consortia acknowledgements is included in the Additional file 2 : Acknowledgements. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: C.J.B. is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). Funding Information: KKT is supported by Cancer Research UK (PPRCPJT\100005) Funding Information: E.E.V. is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Funding Information: This work was supported by Cancer Research UK (C18281/A29019) Publisher Copyright: © 2022, The Author(s).

PY - 2023/1/4

Y1 - 2023/1/4

N2 - BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

AB - BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

KW - Adult

KW - Humans

KW - Child

KW - Middle Aged

KW - Adiposity/genetics

KW - Pediatric Obesity

KW - Risk Factors

KW - Mendelian Randomization Analysis

KW - Genome-Wide Association Study

KW - Body Mass Index

KW - Colonic Neoplasms

KW - Polymorphism, Single Nucleotide

U2 - 10.1186/s12916-022-02702-9

DO - 10.1186/s12916-022-02702-9

M3 - Article (Academic Journal)

C2 - 36600297

SN - 1741-7015

VL - 21

SP - 5

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 5

ER -

Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Abstract

Bibliographical note

UN SDGs

Research Groups and Themes

Keywords

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this