Comparison of caffeine consumption behavior with plasma caffeine levels as exposures in drug-target Mendelian randomization and implications for interpreting effects on obesity

Drug-target Mendelian randomization (MR) is a popular approach for exploring the effects of pharmacological targets. Cis-MR designs select variants within the gene region that code for a protein of interest to mimic pharmacological perturbation. An alternative uses variants associated with behavioral proxies of target perturbation, such as drug usage. Both have been employed to investigate the effects of caffeine but have drawn different conclusions. We use the effects of caffeine on body mass index (BMI) as a case study to highlight two potential flaws of the latter strategy in drug-target MR: misidentifying the exposure and using invalid instruments. Some variants associate with caffeine consumption because of their role in caffeine metabolism. Since people with these variants require less caffeine for the same physiological effect, the direction of the caffeine-BMI association is flipped depending on whether estimates are scaled by caffeine consumption or plasma caffeine levels. Other variants seem to associate with caffeine consumption via behavioral pathways. Using multivariable-MR, we demonstrate that caffeine consumption behavior influences BMI independently of plasma caffeine. This implies the existence of behaviorally mediated exclusion restriction violations. Our results support the superiority of cis-MR study designs in pharmacoepidemiology over the use of behavioral proxies of drug targets.