STROBE checklist.

<div> Background Adverse drug reactions (ADRs) harm patients and are costly for healthcare systems. Genetic variation contributes to variability in medication response and prospective knowledge of these variants can decrease risk of ADRs, as shown in the PREPARE trial. Reduction in ADRs would affect only those reactions to drugs contained in well-validated pharmacogene–drug pairs. The scope of ADRs represented by these drugs on a population scale is unclear. The objective of this study was to characterize the pharmacogene–drug-associated ADR reporting landscape from a national regulatory pharmacovigilance dataset to elucidate the scale of potential ADR mitigation by pharmacogenomics (PGx) implementation. Methods and findings All publicly available Yellow Card ADR reports to the United Kingdom Medicines and Healthcare Products Regulatory Agency, from 1963 to 2024, were compiled using programmatic data extraction. The ADRs were analysed with descriptive statistics, stratified by PGx status and by associated genes. Prescribing prevalence from the literature was compared with age range matched ADR reports for PGx-associated drugs. There were 1,345,712 ADR reports, attributed to 2,499 different substances. 115,789 adverse drug reports (9%) were associated with drugs for which ADR risk can be modified based on pharmacogenomic prescribing guidance. Seventy-five percent of these (<i>n</i> = 87,339) were due to medicines which interact with only three pharmacokinetic pharmacogenes (<i>CYP2C19</i>, <i>CYP2D6</i>, <i>SLCO1B1</i>). Forty-seven percent of all the PGx mitigatable ADRs identified were attributed to psychiatric medications (<i>n</i> = 54,846), followed by 24% attributed to cardiovascular medications (<i>n</i> = 28,279). Those experiencing PGx mitigatable ADRs, as compared with non-PGx mitigatable ADRs, were older and the ADRs more often consisted of severe non-fatal reactions. Many PGx-associated psychiatric drug ADRs were overrepresented as compared with prescribing prevalence, but fatal cardiac arrhythmias were uncommon consequences, comprising only 0.4% of these ADRs (<i>n</i> = 172 of <i>n</i> = 48,315 total ADRs). Limitations of this data source include under reporting of ADRs and reporting bias. These findings are based on analysis of the Yellow Card dataset described and may not represent all ADRs from a generalised patient population. Conclusions Nine percent of all reported ADRs are associated with drugs where a genetic variant can cause heightened risk of an ADR and inform prescribing. A panel of only three pharmacogenes could potentially mitigate three in every four PGx modifiable ADRs. Based on our findings, Psychiatry may be the single highest impact specialty to pilot PGx to reduce ADRs and associated morbidity, mortality and costs. </div>