Human genetic evidence enriched for side effects of approved drugs

Safety failures are an important factor in low drug development success rates. Human genetic evidence can select drug targets causal in disease and enrich for successful programs. Here, we sought to determine whether human genetic evidence can also enrich for labeled side effects (SEs) of approved drugs. We combined the SIDER database of SEs with human genetic evidence from genome-wide association studies, Mendelian disease, and somatic mutations. SEs were 2.0 times more likely to occur for drugs whose target possessed human genetic evidence for a trait similar to the SE. Enrichment was highest when the trait and SE were most similar to each other, and was robust to removing drugs where the approved indication was also similar to the SE. The enrichment of genetic evidence was greatest for SEs that were more drug specific, affected more people, and were more severe. There was significant heterogeneity among disease areas the SEs mapped to, with the highest positive predictive value for cardiovascular SEs. This supports the integration of human genetic evidence early in the drug discovery process to identify potential SE risks to be monitored or mitigated in the course of drug development. ### Competing Interest Statement MRN is an employee of Genscience and Deerfield. EVM is a consultant to Deerfield. EVM also acknowledges research support, unrelated to the current work, from Ionis, Gate, and Charles River. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript, the supplementary tables, or the public GitHub site at https://github.com/ericminikel/genetics\_side\_effects/ [https://github.com/ericminikel/genetics\_side\_effects/][1] [1]: https://github.com/ericminikel/genetics_side_effects/