risk but not on alcohol consumption82, 120. Although these studies provided novel insights useful to understand the mechanisms underlying comorbidities of SUDs, MR analyses present several limitations that should be considered carefully when interpreting their findings in the context of SUDs and other complex traits. Each MR design is based on specific assumptions121. Although several kinds of sensitivity analyses can be employed to evaluate possible biases122, it is hard to determine whether other unaccounted confounders are affecting the results. Additionally, the low SNP-based heritability, the high polygenicity, and the complex pleiotropy of SUD-related traits strongly affect the statistical power and realiability of MR methods. Other analytical approaches therefore need to be used to extend and validate MR results. Longitudinal studies can be a viable option although they also present certain limitations123. The gold standard for causal inference remain randomized controlled trials. However, there are several issues (e.g., ethical quandaries) that limit their application to SUD research.
