Supplementary file 1_Opportunities to improve open All of Us data to convey CYP2D6 pharmacological relevance and interpretation overall and according to ancestry.pdf

IntroductionCYP2D6 is a highly polymorphic gene with significant pharmacogenomic and public health implications. Understanding the population distribution of CYP2D6 variants offers opportunities to enhance awareness of its pharmacological relevance, particularly across different ancestral groups.
MethodsUsing the National Institute of Health All of Us Research Program Data Browser, we identified CYP2D6 alleles with a frequency ≥0.10 in the overall cohort or within ancestral subgroups and classified in ClinVar as having either “drug response” or “undefined” significance. We assessed alleles with frequency differences ≥0.10 between ancestral subgroups and the overall population to highlight subgroup-specific pharmacogenomic relevance. CYP2D6 alleles with ClinVar “undefined” significance classifications were cross-referenced with expert pharmacological resources [e.g., Pharmacogene Variation (PharmVar) Consortium] to identify candidates for reclassification as “drug response” significance variants.
ResultsAmong the 89 CYP2D6 alleles with ClinVar “drug response” significance classification, 7 of 11 (64%) were more frequent (≥0.10) in the East Asian ancestry subgroup than in the overall population. Among 6,262 CYP2D6 alleles with “undefined” significance classification, 60 showed elevated frequencies (≥0.10) in at least one subgroup: Middle Eastern (31/60; 52%), African (22/60; 37%), East Asian (21/60; 35%), and South Asian (4/60; 7%) ancestries. Of these 60 alleles, 16 (27%) map to 41–76 star allele haplotypes that contain at least one sub-allele with “definitive” allele evidence levels in PharmVar.
ConclusionOur findings highlight the differential distribution and potential pharmacological relevance of CYP2D6 alleles across ancestral subgroups. These insights support potential reclassification of certain “undefined” alleles and highlight the importance of inclusive pharmacogenomic research to improve population-specific drug response knowledge.