Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size

Grace M Power; Jessica Tyrrell; Timothy Frayling; George Davey Smith; Tom G Richardson

doi:10.1161/JAHA.121.021503

Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size

Grace M Power^*, Jessica Tyrrell, Timothy Frayling, George Davey Smith, Tom G Richardson

^*Corresponding author for this work

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

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Abstract

Background: Obesity is associated with long-term health consequences including cardiovascular disease (CVD). Separating the independent effects of childhood and adulthood obesity on CVD risk is challenging as children with obesity typically remain overweight throughout the lifecourse.

Methods and Results: This study used two-sample univariable and multivariable mendelian randomisation (MR) to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the CVD disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable MR, suggesting that childhood body size indirectly increases risk of these eight disease outcomes via the pathway involving adult body size.

Conclusions: These findings suggest that the effect of genetically predicted childhood body size on the CVD outcomes analysed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where the detrimental impact of obesity initiated in early life begins to become immutable.

Original language	English
Article number	e021503
Pages (from-to)	e021503
Journal	Journal of the American Heart Association
Volume	10
Issue number	17
DOIs	https://doi.org/10.1161/JAHA.121.021503
Publication status	Published - 7 Sept 2021

Bibliographical note

Funding Information:
This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by grant MR/N0137941/1 for the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council (MRC)/UKRI. Richardson was a UK Research and Innovation Innovation Research Fellow while contributing to this study (MR/S003886/1). Frayling has received funding from the Medical Research Council, MR/T002239/1 and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and T1D Exchange, JDRF, and Obesity Action Coalition. Tyrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079).

Funding Information:
This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by grant MR/N0137941/1 for the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council (MRC)/UKRI. Richardson was a UK Research and Innovation Innovation Research Fellow while contributing to this study (MR/S003886/1). Frayling has received funding from the Medical Research Council, MR/T002239/1 and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. This Joint Undertaking receives support from the European Union?s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and T1D Exchange, JDRF, and Obesity Action Coalition. Tyrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079).

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© 2021 The Authors.

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JAHA.121.021503
This is the final published version of the article (version of record). It first appeared online via Wiley at 10.1161/JAHA.121.021503. Please refer to any applicable terms of use of the publisher.
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@article{3ffc03aa18d048bd82fdc6142538a9d0,

title = "Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size",

abstract = "Background: Obesity is associated with long-term health consequences including cardiovascular disease (CVD). Separating the independent effects of childhood and adulthood obesity on CVD risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results: This study used two-sample univariable and multivariable mendelian randomisation (MR) to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the CVD disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable MR, suggesting that childhood body size indirectly increases risk of these eight disease outcomes via the pathway involving adult body size. Conclusions: These findings suggest that the effect of genetically predicted childhood body size on the CVD outcomes analysed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where the detrimental impact of obesity initiated in early life begins to become immutable.",

author = "Power, {Grace M} and Jessica Tyrrell and Timothy Frayling and {Davey Smith}, George and Richardson, {Tom G}",

note = "Funding Information: This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by grant MR/N0137941/1 for the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council (MRC)/UKRI. Richardson was a UK Research and Innovation Innovation Research Fellow while contributing to this study (MR/S003886/1). Frayling has received funding from the Medical Research Council, MR/T002239/1 and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and T1D Exchange, JDRF, and Obesity Action Coalition. Tyrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). Funding Information: This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by grant MR/N0137941/1 for the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council (MRC)/UKRI. Richardson was a UK Research and Innovation Innovation Research Fellow while contributing to this study (MR/S003886/1). Frayling has received funding from the Medical Research Council, MR/T002239/1 and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. This Joint Undertaking receives support from the European Union?s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and T1D Exchange, JDRF, and Obesity Action Coalition. Tyrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). Publisher Copyright: {\textcopyright} 2021 The Authors.",

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Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size. / Power, Grace M; Tyrrell, Jessica; Frayling, Timothy et al.
In: Journal of the American Heart Association, Vol. 10, No. 17, e021503, 07.09.2021, p. e021503.

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

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T1 - Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size

AU - Power, Grace M

AU - Tyrrell, Jessica

AU - Frayling, Timothy

AU - Davey Smith, George

AU - Richardson, Tom G

N1 - Funding Information: This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by grant MR/N0137941/1 for the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council (MRC)/UKRI. Richardson was a UK Research and Innovation Innovation Research Fellow while contributing to this study (MR/S003886/1). Frayling has received funding from the Medical Research Council, MR/T002239/1 and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and T1D Exchange, JDRF, and Obesity Action Coalition. Tyrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). Funding Information: This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by grant MR/N0137941/1 for the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council (MRC)/UKRI. Richardson was a UK Research and Innovation Innovation Research Fellow while contributing to this study (MR/S003886/1). Frayling has received funding from the Medical Research Council, MR/T002239/1 and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875534. This Joint Undertaking receives support from the European Union?s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations and T1D Exchange, JDRF, and Obesity Action Coalition. Tyrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). Publisher Copyright: © 2021 The Authors.

PY - 2021/9/7

Y1 - 2021/9/7

N2 - Background: Obesity is associated with long-term health consequences including cardiovascular disease (CVD). Separating the independent effects of childhood and adulthood obesity on CVD risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results: This study used two-sample univariable and multivariable mendelian randomisation (MR) to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the CVD disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable MR, suggesting that childhood body size indirectly increases risk of these eight disease outcomes via the pathway involving adult body size. Conclusions: These findings suggest that the effect of genetically predicted childhood body size on the CVD outcomes analysed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where the detrimental impact of obesity initiated in early life begins to become immutable.

AB - Background: Obesity is associated with long-term health consequences including cardiovascular disease (CVD). Separating the independent effects of childhood and adulthood obesity on CVD risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results: This study used two-sample univariable and multivariable mendelian randomisation (MR) to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the CVD disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable MR, suggesting that childhood body size indirectly increases risk of these eight disease outcomes via the pathway involving adult body size. Conclusions: These findings suggest that the effect of genetically predicted childhood body size on the CVD outcomes analysed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where the detrimental impact of obesity initiated in early life begins to become immutable.

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DO - 10.1161/JAHA.121.021503

M3 - Article (Academic Journal)

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SN - 2047-9980

VL - 10

SP - e021503

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 17

M1 - e021503

ER -

Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size

Abstract

Bibliographical note

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

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