A recent population-based cohort study found an association between proton pump inhibitor (PPI) prescription and risk of inflammatory bowel disease which they attributed to protopathic bias (ie, the drug was prescribed in response to initial disease symptoms) rather than a causal effect of PPI usage.1 In a following Mendelian randomisation (MR) study, An et al selected genetic variants associated with PPI usage to proxy the effect of exposure to PPI treatment.2 However, interpretation of these results remains unclear due to concerns about the strategy for instrumental variable selection identifies genetic variants that mimic the treatment under investigation. The fundamental concern is the difference between genetic predictors of the drug target effect versus genetic predictors of taking the drug.

The major concern is that the association between genetic variants and drug use likely stems from their potential to exacerbate the underlying condition targeted by the drug or to intensify associated symptoms. For example, the variant rs11591147 in the PCSK9 gene region is associated with an increased use of cholesterol-lowering medication but also higher levels of cholesterol.3 We also found contradictory results between genetically predicted medication usage behaviour and genetically predicted drug target effect …