Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits

Background: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding. Methods: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data. Results: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits. Conclusions: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.