GWAS data can be used to assess causal mechanisms by applying Mendelian randomization (MR). MR is an instrumental variables technique that uses genetic variants to index if an observational association between a risk factor (e.g. MD) and an outcome (e.g. AD) is consistent with a causal effect (e.g. MD causes AD). MR relies on random assortment of genetic variants during meiosis which are typically unassociated with confounders since they are randomly distributed in the population at birth. The differences in outcome between those who carry genetic risk variants and those who do not can be attributed to the difference in the risk factor. The validity of the genetic instrument is dependent on meeting three core assumptions: (i) the genetic variant is associated with the risk factor/exposure; (ii) the genetic variant is not associated with confounders; and (iii) the genetic variant influences the outcome only through the risk factor. Although random controlled trials (RCTs) are considered the gold standard for establishing causality, MR is a viable alternative to provide support for causal mechanisms, especially when RCTs are not possible or ethical.
