Population prevalence of high-risk pharmacogenetic configurations in a healthy older Australian reference cohort

Recent advances in pharmacogenomic guidelines, regulatory labelling, and clinical implementation are supporting broader adoption of pharmacogenetic testing. We analysed whole-genome sequencing data from 3,205 participants in the Medical Genome Reference Bank, a healthy older Australian reference cohort predominantly of European ancestry, to characterise established and novel pharmacogenetic variation. Overall, 1,303 participants (40.7%) carried at least one confirmed homozygous ClinPGx/PharmGKB Level 1A high-risk configuration. A further 399 participants (12.4%) carried at least one potential-trans, phase-unresolved configuration. After accounting for overlap, 1,566 participants (48.9%) had either a confirmed homozygous or potential-trans, phase-unresolved configuration, representing an upper-bound estimate of potential biallelic involvement rather than confirmed biallelic prevalence. Confirmed homozygous configurations occurred in two or more high-risk pharmacogenes in 255 participants (8.0%) and in three or more genes in 22 participants (0.7%); the corresponding upper-bound estimates were 377 (11.8%) and 45 (1.4%), respectively. None of 409 candidate potential-trans participant-gene configurations could be directly resolved as cis or trans from available phase information. A total of 140 novel predicted loss-of-function participant-gene category records were identified across the high-risk pharmacogene set. Within CYP2D6, 277 participants (8.6%) carried confirmed homozygous Level 1A configurations, although these rsID-defined findings do not represent a complete estimate of CYP2D6 metaboliser-phenotype prevalence. Exploratory structural modelling of selected OPRM1 missense variants identified variation in predicted fentanyl docking scores and receptor-ligand contact geometry, although these findings require experimental validation. These results demonstrate the value of population-scale whole-genome sequencing for pharmacogenomic discovery while highlighting the importance of distinguishing confirmed homozygous findings from phase-unresolved multi-variant configurations.