A functional ancestry-linked regulatory haplotype influences CYP2D6 expression

Cytochrome P450 (CYP) enzymes metabolize 70-80% of therapeutic agents, yet regulatory variants affecting drug metabolism remain poorly characterized across populations. Although numerous studies have examined coding variants in pharmacogenes, comprehensive analysis of regulatory variation across tissues and ancestries is lacking. Expression quantitative trait loci (eQTLs) for 54 CYP genes were analyzed using GTEx data, identifying CYP2D6 as harboring the most extensive regulatory variation, with 249 variants including two high-effect variants in strong linkage disequilibrium. In silico functional analysis predicts that one variant disrupts thousands of transcription factor binding sites in a region of high chromatin accessibility. Both variants exhibit population stratification, occurring at 45% frequency in East Asian populations versus 2.5% in Europeans, and show strong linkage with the reduced-function CYP2D6*10 allele. These results indicate that ancestry-specific regulatory variants should be incorporated into pharmacogenetic testing strategies.