Distribution of the J1 haplotype variant rs2267439 across CYP2D6 diplotypes and its impact on risperidone metabolism

CYP2D6 is a highly polymorphic pharmacogene responsible for the metabolism of more than 20% of commonly prescribed drugs. Clinical implementation of CYP2D6 pharmacogenetics relies on star allele nomenclature and the Activity Score system, yet substantial interindividual variability in drug exposure remains unexplained. A recent study proposed that the so-called J1 haplotype, defined by rs2267439 C>T located 285 kb downstream of CYP2D6 , improves phenotype prediction when combined with revised activity values for selected alleles. However, accurate resolution of the phase of the J1 variant with star alleles requires long-read sequencing due to the distant genomic location of rs2267439 from the gene. In this study, we used phased long-read sequencing data from 884 pediatric subjects to characterize the distribution of the J1-defining variant across CYP2D6 star alleles. Additionally, we evaluated the functional impact of the variants defining the J1, L, and O1 unphased haplotypes on risperidone metabolism in a Nigerian cohort of 125 patients treated with risperidone using targeted genotyping. Phased long-read sequencing revealed that the J1/rs2267439 variant is broadly distributed across CYP2D6 star alleles of all functional categories (normal, decreased, and no function) without preferential co-segregation with any specific allele. In the risperidone-treated African unphased cohort, J1, L, and O1-defining variants were highly prevalent, yet none were associated with statistically significant differences in risperidone metabolic ratios across CYP2D6*1/*1 , *1/*2 , or *1/*29 diplotype groups. These findings suggest that testing the J1, L, and O1-defining variants may not improve CYP2D6 -based phenotype prediction for risperidone. Incorporation of these variants into clinical guidelines requires further validation across diverse populations and multiple substrates.