Genetic inference of on-target and off-target side-effects of antipsychotic medications

It is often difficult to ascertain whether patient-reported side-effects are caused by a drug, and if so, through which mechanism. Adverse side-effects are the primary cause of antipsychotic drug discontinuation rather than poor efficacy. Using a novel method combining genetic and drug binding affinity data, we investigated evidence of causal mechanisms for 80 reported side-effects of 6 commonly prescribed antipsychotic drugs which together target 68 receptors. We analysed publicly available drug binding affinity data and genetic association data using Mendelian randomization and genetic colocalization to devise a representative ‘score’ for each combination of drug, side-effect, and receptor. We show that 36 side-effects are likely caused by drug action through 30 receptors, which are mainly attributable to off-target effects (26 off-target receptors underlying 39 side-effects). This method allowed us to distinguish which reported side-effects have evidence of causality. Of individual drugs, clozapine has the largest cumulative side-effect profile (Score = 57.5, SE = 11.2), and the largest number of side-effects (n = 36). We show that two well-known side-effects for clozapine, neutropenia and weight change, are underpinned by the action of GABA and CHRM3 receptors respectively. Our novel genetic approach can map side-effects to drugs and elucidate underlying mechanisms, which could potentially inform clinical practice, drug repurposing, and pharmacological development. Further, this method can be generalized to infer the on-target and off-target effects of drugs at any stage of the drug development pipeline.