Genomics-first association of pharmacogenomic risk phenotypes with adverse drug reactions in a healthcare-based population.

PURPOSE: Pharmacogenomic (PGx) variation affects drug metabolism and adverse drug reaction (ADR) risk. While the Clinical Pharmacogenetics Implementation Consortium (CPIC) lists 573 actionable gene-drug pairs, large-scale evaluation of PGx-related ADRs remains limited. We performed a retrospective genomic-first analysis on genetic and electronic health record (EHR) data to assess PGx impact on ADR risk. METHODS: We analyzed 226,053 individuals in the Geisinger MyCode cohort for 58 CPIC high-risk gene-drug associations spanning 11 genes. Genetic findings were linked to EHR allergy and medication discontinuation records. RESULTS: Most individuals (211,920/226,053, 93.7%) had at least one actionable PGx phenotype and 44.4% (100,402/226,053) had an actionable phenotype conferring ADR risk and were prescribed a relevant medication. As individuals accumulate medication exposures, ADR incidence increases (Pearson's correlation=0.50, P<0.001). Individuals with risk phenotypes were more likely to have a documented allergy or ADR-related medication discontinuation (P<0.001, OR=1.4), and 3.9% (8,913/226,053) exhibited an ADR associated with personal PGx risk. We observed 36,194 ADRs across 27,546 individuals (12.2% of cohort); 10,719/36,194 (29.6%) occurred in individuals with relevant PGx phenotypes. CONCLUSION: Individuals exposed to more medications exhibit increased ADR rates. PGx further compounds ADR risk, and a portion of population ADR burden could possibly have been prevented through PGx-guided therapy.