Genetic ancestral patterns in CYP2D6 alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes

Cytochrome P450 2D6 (CYP2D6) is involved in metabolising over 20% of clinical drugs, yet its genetic variation across ancestries is underexplored in large-scale whole-genome sequencing (WGS) datasets. We analysed WGS data from 479,144 UK Biobank participants, identifying 95 distinct CYP2D6 star alleles across five biogeographic groups. Of these, 48 alleles had currently unknown effects. These alleles were more prevalent in African, admixed American, and South Asian groups ([~]5%) compared to European and East Asian groups ([~]2%), affecting the ability to provide pharmacogenomics recommendations across ancestries. We identified 99,656 (20.8%) individuals carrying CYP2D6 structural variations and predicted the CYP2D6 ultra-rapid metaboliser phenotype to be most common in Africans (4.5%) and rarest in East Asians (0.32%). Less than half (45.7%) of rare protein-truncating variant carriers were categorised as poor or intermediate metabolisers, indicating an underrepresentation of rare functional variants in the current CYP2D6 star allele evaluation. Phenome-wide association studies confirmed links with narcotic allergies and found new associations with plasma BAFFR and BAFF proteins, offering insights for the BAFF-targeted clinical therapy. Collectively, this largest WGS study of CYP2D6 to date highlights the importance of leveraging all genetic variations for pharmacogenomic insights affecting therapeutic safety and development.