University of Oulu

Tom G Richardson, Juha Mykkänen, Katja Pahkala, Mika Ala-Korpela, Joshua A Bell, Kurt Taylor, Jorma Viikari, Terho Lehtimäki, Olli Raitakari, George Davey Smith, Evaluating the direct effects of childhood adiposity on adult systemic metabolism: a multivariable Mendelian randomization analysis, International Journal of Epidemiology, Volume 50, Issue 5, October 2021, Pages 1580–1592, https://doi.org/10.1093/ije/dyab051

Evaluating the direct effects of childhood adiposity on adult systemic metabolism : a multivariable Mendelian randomization analysis

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Author: Richardson, Tom G1; Mykkänen, Juha2,3; Pahkala, Katja2,3,4;
Organizations: 1MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
2Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
3Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
4Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, University of Turku, Turku, Finland
5Computational Medicine, Center for Life Course Health Research, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
6NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
7Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland
8Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research CenterTampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
9Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022020717907
Language: English
Published: Oxford University Press, 2021
Publish Date: 2022-02-07
Description:

Abstract

Background: Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways.

Methods: Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls.

Results: Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P < 4.07 × 10−4). However, the majority of these effects (35/42) substantially attenuated when accounting for adult body size using multivariable MR. We found little evidence that the biomarkers that were potentially influenced directly by childhood body size (leucine, isoleucine and tyrosine) mediate this effect onto adult disease risk. Very-low-density lipoprotein markers provided the strongest evidence of mediating the long-term effect of adiposity on CAD risk.

Conclusions: Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.

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Series: International journal of epidemiology
ISSN: 0300-5771
ISSN-E: 1464-3685
ISSN-L: 0300-5771
Volume: 50
Issue: 5
Pages: 1580 - 1592
DOI: 10.1093/ije/dyab051
OADOI: https://oadoi.org/10.1093/ije/dyab051
Type of Publication: A1 Journal article – refereed
Field of Science: 3141 Health care science
Subjects:
Funding: 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]. GDS 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. T.G.R. is a UKRI Innovation Research Fellow [MR/S003886/1]. J.A.B. is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund [204813/Z/16/Z]. K.T. is supported by a British Heart Foundation Doctoral Training Program [FS/17/60/33474]. The Special Turku Coronary Risk Factor Intervention Project study is funded by the Academy of Finland [grants 206374, 294834, 251360, 275595 and 322112], the Juho Vainio Foundation, the Finnish Foundation for Cardiac Research, the Finnish Ministry of Education and Culture, the Finnish Cultural Foundation, the Sigrid Jusélius Foundation, Special Governmental Grants for Health Sciences Research (Turku University Hospital), the Yrjö Jahnsson Foundation and the Turku University Foundation. The Young Finns Study is funded by the Academy of Finland [grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi) and 322098 (for T.L.)]; the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals [grant X51001]; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Jusélius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 [grant 755320 for TAXINOMISIS and grant 848146 To-Aition]; and European Research Council [grant 742927 for MULTIEPIGEN project]; Tampere University Hospital Supporting Foundation. M.A.K. is funded by a research grant from the Sigrid Jusélius Foundation, Finland.
Academy of Finland Grant Number: 294834
Detailed Information: 294834 (Academy of Finland Funding decision)
Dataset Reference: Supplementary data are available at IJE online. Further information regarding data from the Young Finns Study, as well as proposals for collaboration and data access, can be requested by contacting Prof. Olli Raitakari. Genetic instruments on childhood and adult body size were obtained from the previous study by Richardson et al. (2020) using data from the UK Biobank study (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). Metabolites GWAS data are publicly available at http://www.computationalmedicine.fi/data/NMR_GWAS/. Publicly available GWAS data on coronary artery disease were obtained from http://www.cardiogramplusc4d.org/data-downloads/. All other GWAS data are publicly available at https://gwas.mrcieu.ac.uk/.
  https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access
http://www.computationalmedicine.fi/data/NMR_GWAS/
http://www.cardiogramplusc4d.org/data-downloads/
https://gwas.mrcieu.ac.uk/
https://academic.oup.com/ije/article/50/5/1580/6202983#supplementary-data
Copyright information: © The Author(s) 2021. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/