Genet Epidemiol. 2026 Feb;50(1):e70031. doi: 10.1002/gepi.70031.
ABSTRACT
A longstanding aim of developmental psychology and epidemiology is to understand the causal effects of parental phenotypes on offspring outcomes. Traditional approaches often fail to account for confounding and reverse causation. We evaluate the use of Mendelian randomisation with non-inherited variants (MR-NIV) to address these limitations. MR-NIV leverages non-inherited genetic variants to instrument the parental phenotype independent of the offspring’s genotype. We used Directed Acyclic Graphs and simulations to validate MR-NIV and explore robustness to assortative mating. In contrast to an alternative MR method which adjusts the parental genotype for offspring genotype, MR-NIV can be robust to assortative mating when used without trio data. In settings without trio data, MR-NIV outperformed the adjustment method. The adjustment method outperformed MR-NIV in settings with trio data. Applying MR-NIV to the Avon Longitudinal Study of Parents and Children, we assessed the causal effect of parental smoking on offspring smoking initiation at age 16. Results were consistent with observational studies, suggesting a meaningful increase in the risk of offspring smoking due to parental smoking. However, larger sample sizes will be necessary to provide a precise answer. MR-NIV offers a promising extension of Mendelian randomisation for studying the developmental environment.
PMID:41562185 | DOI:10.1002/gepi.70031
