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A cautionary note on using Mendelian randomization to examine the Barker hypothesis and Developmental Origins of Health and Disease (DOHaD)

Published online by Cambridge University Press:  04 December 2020

Shannon D’Urso Open the ORCID record for Shannon D’Urso [Opens in a new window] ,
Geng Wang ,
Liang-Dar Hwang ,
Gunn-Helen Moen ,
Nicole M. Warrington  and
David M. Evans
Shannon D’Urso
Affiliation:
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia
Geng Wang
Affiliation:
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia
Liang-Dar Hwang
Affiliation:
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia
Gunn-Helen Moen
Affiliation:
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
Nicole M. Warrington
Affiliation:
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
David M. Evans*
Affiliation:
The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
*
Address for correspondence: David M. Evans, University of Queensland Diamantina Institute, Level 7, 37 Kent St, Translational Research Institute, Woolloongabba, QLD4102, Australia. Email: [email protected]
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Abstract

Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms; where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.

Keywords

Mendelian randomizationcausal inferencetype 2 diabetescardiometabolic diseaseconditional analysisBarker hypothesisDevelopmental Origins of Health and Disease
Type
Brief Reports
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 5 , October 2021 , pp. 688 - 693
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Copyright
© The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

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