Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization – BMC Medicine
Background Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism. Methods Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization. Results Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confide