Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

Tom G Richardson; Daniel Crouch; Grace Marion Power; Fernanda Morales Berstein; Emma Hazelwood; Si Fang; Yoonsu Cho; Jamie Inshaw; Catherine Robertson; Carlo Sidore; Francesco Cucca; Steven Rich; John Todd; George Davey Smith

doi:10.1038/s41467-022-29932-y

Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

Tom G Richardson^*, Daniel Crouch, Grace Marion Power, Fernanda Morales Berstein, Emma Hazelwood, Si Fang, Yoonsu Cho, Jamie Inshaw, Catherine Robertson, Carlo Sidore, Francesco Cucca, Steven Rich, John Todd, George Davey Smith

^*Corresponding author for this work

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Abstract

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggest that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Original language	English
Article number	2337
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	28 Apr 2022
DOIs	https://doi.org/10.1038/s41467-022-29932-y
Publication status	E-pub ahead of print - 28 Apr 2022

Bibliographical note

Funding Information:
We thank the authors and GWAS consortia who made their summary statistics available for the benefit of this study. This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). G.D.S. conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol 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. TGR was a UKRI Innovation Research Fellow (MR/S003886/1) whilst undertaking this project. G.M.P. 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. S.F. and F.M.-B. are supported by Wellcome Trust PhD studentships in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z and 218495/Z/19/Z, respectively]. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genetic data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.?The work of D.J.M.C., J.R.J.I. and J.A.T. was supported by the JDRF [9-2011-253], [5-SRA-2015-130-A-N], [4-SRA-2017-473-A-N]; the Wellcome [091157/Z/10/Z], [107212/Z/15/Z]; [203141/Z/16/Z]. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Funding Information:
We thank the authors and GWAS consortia who made their summary statistics available for the benefit of this study. This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). G.D.S. conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol 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. TGR was a UKRI Innovation Research Fellow (MR/S003886/1) whilst undertaking this project. G.M.P. 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. S.F. and F.M.-B. are supported by Wellcome Trust PhD studentships in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z and 218495/Z/19/Z, respectively]. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genetic data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The work of D.J.M.C., J.R.J.I. and J.A.T. was supported by the JDRF [9-2011-253], [5-SRA-2015-130-A-N], [4-SRA-2017-473-A-N]; the Wellcome [091157/Z/10/Z], [107212/Z/15/Z]; [203141/Z/16/Z]. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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

Keywords

Childhood adiposity
Type 1 diabetes
Mendelian randomization
chronic immune-associated diseases
inflammation
B-cell fragility
ALSPAC

UN SDGs

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

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Richardson, T. G., Crouch, D., Power, G. M., Morales Berstein, F., Hazelwood, E., Fang, S., Cho, Y., Inshaw, J., Robertson, C., Sidore, C., Cucca, F., Rich, S., Todd, J., & Davey Smith, G. (2022). Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach. Nature Communications, 13(1), Article 2337 . Advance online publication. https://doi.org/10.1038/s41467-022-29932-y

@article{bf503ab8a89243e6b8bed21c424467da,

title = "Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach",

abstract = "The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggest that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.",

keywords = "Childhood adiposity, Type 1 diabetes, Mendelian randomization, chronic immune-associated diseases, inflammation, B-cell fragility, ALSPAC",

author = "Richardson, {Tom G} and Daniel Crouch and Power, {Grace Marion} and {Morales Berstein}, Fernanda and Emma Hazelwood and Si Fang and Yoonsu Cho and Jamie Inshaw and Catherine Robertson and Carlo Sidore and Francesco Cucca and Steven Rich and John Todd and {Davey Smith}, George",

note = "Funding Information: We thank the authors and GWAS consortia who made their summary statistics available for the benefit of this study. This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). G.D.S. conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol 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. TGR was a UKRI Innovation Research Fellow (MR/S003886/1) whilst undertaking this project. G.M.P. 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. S.F. and F.M.-B. are supported by Wellcome Trust PhD studentships in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z and 218495/Z/19/Z, respectively]. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genetic data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.?The work of D.J.M.C., J.R.J.I. and J.A.T. was supported by the JDRF [9-2011-253], [5-SRA-2015-130-A-N], [4-SRA-2017-473-A-N]; the Wellcome [091157/Z/10/Z], [107212/Z/15/Z]; [203141/Z/16/Z]. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: We thank the authors and GWAS consortia who made their summary statistics available for the benefit of this study. This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). G.D.S. conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol 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. TGR was a UKRI Innovation Research Fellow (MR/S003886/1) whilst undertaking this project. G.M.P. 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. S.F. and F.M.-B. are supported by Wellcome Trust PhD studentships in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z and 218495/Z/19/Z, respectively]. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genetic data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The work of D.J.M.C., J.R.J.I. and J.A.T. was supported by the JDRF [9-2011-253], [5-SRA-2015-130-A-N], [4-SRA-2017-473-A-N]; the Wellcome [091157/Z/10/Z], [107212/Z/15/Z]; [203141/Z/16/Z]. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41467-022-29932-y",

language = "English",

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Richardson, TG, Crouch, D, Power, GM , Morales Berstein, F , Hazelwood, E , Fang, S, Cho, Y, Inshaw, J, Robertson, C, Sidore, C, Cucca, F, Rich, S, Todd, J & Davey Smith, G 2022, 'Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach', Nature Communications, vol. 13, no. 1, 2337 . https://doi.org/10.1038/s41467-022-29932-y

TY - JOUR

T1 - Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

AU - Richardson, Tom G

AU - Crouch, Daniel

AU - Power, Grace Marion

AU - Morales Berstein, Fernanda

AU - Hazelwood, Emma

AU - Fang, Si

AU - Cho, Yoonsu

AU - Inshaw, Jamie

AU - Robertson, Catherine

AU - Sidore, Carlo

AU - Cucca, Francesco

AU - Rich, Steven

AU - Todd, John

AU - Davey Smith, George

N1 - Funding Information: We thank the authors and GWAS consortia who made their summary statistics available for the benefit of this study. This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). G.D.S. conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol 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. TGR was a UKRI Innovation Research Fellow (MR/S003886/1) whilst undertaking this project. G.M.P. 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. S.F. and F.M.-B. are supported by Wellcome Trust PhD studentships in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z and 218495/Z/19/Z, respectively]. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genetic data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.?The work of D.J.M.C., J.R.J.I. and J.A.T. was supported by the JDRF [9-2011-253], [5-SRA-2015-130-A-N], [4-SRA-2017-473-A-N]; the Wellcome [091157/Z/10/Z], [107212/Z/15/Z]; [203141/Z/16/Z]. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: We thank the authors and GWAS consortia who made their summary statistics available for the benefit of this study. This work was supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1). G.D.S. conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol 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. TGR was a UKRI Innovation Research Fellow (MR/S003886/1) whilst undertaking this project. G.M.P. 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. S.F. and F.M.-B. are supported by Wellcome Trust PhD studentships in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z and 218495/Z/19/Z, respectively]. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genetic data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The work of D.J.M.C., J.R.J.I. and J.A.T. was supported by the JDRF [9-2011-253], [5-SRA-2015-130-A-N], [4-SRA-2017-473-A-N]; the Wellcome [091157/Z/10/Z], [107212/Z/15/Z]; [203141/Z/16/Z]. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2022, The Author(s).

PY - 2022/4/28

Y1 - 2022/4/28

N2 - The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggest that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

AB - The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggest that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

KW - Childhood adiposity

KW - Type 1 diabetes

KW - Mendelian randomization

KW - chronic immune-associated diseases

KW - inflammation

KW - B-cell fragility

KW - ALSPAC

U2 - 10.1038/s41467-022-29932-y

DO - 10.1038/s41467-022-29932-y

M3 - Article (Academic Journal)

C2 - 35484151

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2337

ER -

Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

Abstract

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Keywords

UN SDGs

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