Elucidating the role of maternal environmental exposures on offspring health and disease using two-sample Mendelian randomization

Abstract

Background: There is considerable interest in estimating the causal effect of a range of maternal environmental exposures on offspring health-related outcomes. Previous attempts to do this using Mendelian randomization methodologies have been hampered by the paucity of epidemiological cohorts with large numbers of genotyped mother-offspring pairs.

Methods: We describe a new statistical model that we have created which can be used to estimate the effect of maternal genotypes on offspring outcomes conditional on offspring genotype, using both individual-level and summary-results data, even when the extent of sample overlap is unknown.

Results: We describe how the estimates obtained from our method can subsequently be used in large-scale two-sample Mendelian randomization studies to investigate the causal effect of maternal environmental exposures on offspring outcomes. This includes studies that aim to assess the causal effect of in utero exposures related to fetal growth restriction on future risk of disease in offspring. We illustrate our framework using examples related to offspring birthweight and cardiometabolic disease, although the general principles we espouse are relevant for many other offspring phenotypes.

Conclusions: We advocate for the establishment of large-scale international genetics consortia that are focused on the identification of maternal genetic effects and committed to the public sharing of genome-wide summary-results data from such efforts. This information will facilitate the application of powerful two-sample Mendelian randomization studies of maternal exposures and offspring outcomes.

Keywords: DOHaD; Developmental Origins of Health and Disease; Fetal Insulin Hypothesis; Maternal effects; Mendelian randomization; birthweight; fetal effects; offspring genetic effects; type 2 diabetes.