Search for common genetic variants to allow reliable Mendelian randomization investigations into ketone metabolism

This study sought common genetic variants that could serve as valid instruments for Mendelian randomization of ketone metabolism, using four stated premises including association with acetone, acetoacetate and beta-hydroxybutyrate and no pleiotropic associations. Lead variants in three of four biologically relevant regions (SLC2A4, HMGCS2, OXCT1) were associated with all three primary ketone bodies. SLC2A4 showed strong pleiotropic associations with blood pressure, and only OXCT1 was also associated with cognitive performance and so satisfied all premises. A separate approach found that genetically predicted acetoacetate, based on seven variants, was associated with improved cognitive performance, but several of those variants were pleiotropic or not in biologically relevant gene regions.