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