Empirical comparisons of multiple Mendelian randomization approaches in the presence of assortative mating

Background Mendelian randomization (MR) is widely used to unravel causal relationships in epidemiological studies. Whereas multiple MR methods have been developed to control for bias due to horizontal pleiotropy, their performance in the presence of other sources of bias, like non-random mating, has been mostly evaluated using simulated data. Empirical comparisons of MR estimators in such scenarios have yet to be conducted. Pleiotropy and non-random mating have been shown to account equally for the genetic correlation between height and educational attainment. Previous studies probing the causal nature of this association have produced conflicting results. Methods We estimated the causal effect of height on educational attainment in various MR models, including the MR-Egger and the MR-Direction of Causation (MR-DoC) models that correct for, or explicitly model, horizontal pleiotropy. Results We reproduced the weak but positive association between height and education in the Netherlands Twin Register sample (P= 3.9 × 10–6). All MR analyses suggested that height has a robust, albeit small, causal effect on education. We showed via simulations that potential assortment for height and education had no effect on the causal parameter in the MR-DoC model. With the pleiotropic effect freely estimated, MR-DoC yielded a null finding. Conclusions Non-random mating may have a bearing on the results of MR studies based on unrelated individuals. Family data enable tests of causal relationships to be conducted more rigorously, and are recommended to triangulate results of MR studies assessing pairs of traits leading to non-random mate selection.