The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that exposures during intrauterine or early infancy development periods have a causal effect on future offspring health. MR has been used to test intrauterine effects by using genetic instrumental variables (IVs) for maternal exposures during pregnancy and exploring their effects on offspring outcomes. Note: DOHaD does not necessarily assume a critical or sensitive periods but rather that exposures in utero are hypothesised to have a lasting effect. Some DOHaD hypotheses do propose that an exposure only has an effect during the intrauterine period (or that any exposure has a stronger effect in utero). For those scenarios, the considerations for MR for testing critical or sensitive periods apply.
As genetic variants are usually identified from genome-wide association studies (GWASs) of men and (non-pregnant) women, it is assumed that these relate to the exposure in women during pregnancy in the same way as they do in the GWAS populations. However, this should be explored where possible as it may not be an appropriate assumption to make in some cases. Offspring genetic variants are a potential source of violation of the exclusion restriction but adjustment for offspring genotype can introduce a spurious association between maternal and paternal genotype (i.e., collider bias). If there is no information on paternal genotype (so it cannot be adjusted for), this can bias the causal effect of maternal pregnancy exposure on offspring outcome if offspring genotype has been adjusted for in the model. Adjustment for offspring and paternal genotype (where available), non-transmitted allele analyses, structural-equation modelling approaches and simulation studies can help explore the extent of bias via offspring genotype.
- Warrington NM, Freathy RM, Neale MC, Evans DM. Using structural equation modelling to jointly estimate maternal and fetal effects on birthweight in the UK Biobank. Int J Epidemiol 2018; 47: 1229-1241.
- Lawlor DA, Richmond R, Warrington N et al. Using Mendelian randomization to determine causal effects of pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them. . Wellcome Open Research 2017; 2: 11.
Other terms in 'Sources of bias and limitations in MR':
- Assortative mating
- Collider bias
- Conditional F-statistic for multiple exposures
- Exclusion restriction assumption
- Harmonization (in two-sample MR)
- Homogeneity Assumption
- Horizontal Pleiotropy
- Independence assumption
- INstrument Strength Independent of Direct Effect (InSIDE) assumption
- Intergenerational (or dynastic) effects
- Monotonicity assumption
- MR for testing critical or sensitive periods
- No effect modification assumption
- NO Measurement Error (NOME) assumption
- Non-linear MR
- Non-overlapping samples (in two-sample MR)
- Population stratification
- Regression dilution bias (attenuation by errors)
- Relevance assumption
- Reverse causality
- Same underlying population (in two-sample MR)
- Statistical power and efficiency
- Vertical pleiotropy
- Weak instrument bias
- Winner's curse