title: Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them.
abstract: Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper, we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of considering the extent to which there is overlap between genetic variants in offspring that influence their outcome with genetic variants used as IVs in their mothers. Where there is overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of IV analyses will be violated. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-sample setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-sample MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted.
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Deborah
authors.identifier: 0000-0002-6793-2262
authors.initials: D
authors.lastname: Lawlor
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Richmond
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.|School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Warrington
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Bowden
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
keywords: ALSPAC; Causality; Mendelian randomization; developmental origins; intrauterine effects