Assessing the capability of massively parallel sequencing for opportunistic pharmacogenetic screening

PURPOSE: To assess exome data for pre-emptive pharmacogenetic screening for 203 clinically-relevant pharmacogenetic variant positions from the Pharmacogenomics Knowledgebase and Clinical Pharmacogenetics Implementation Consortium and identify copy number variants (CNVs) in CYP2D6. METHODS: We examined the coverage and genotype quality of 203 pharmacogenetic variant positions in 973 exomes vs. 5 genomes vs. 5 genotyping chip datasets. Then we determined the agreement of exome and chip genotypes by evaluating concordance in a three-way comparison of exome, genome and chip-based genotyping at 1,929 variant positions in 5 individuals. Finally, we evaluated the utility of exomes for detecting CYP2D6 CNVs. RESULTS: For 5 individuals examined for 203 pharmacogenetic variants (5 × 203 = 1,015), 998/1,015 were identified by genome, 849/1,015 by exome and 295/1,015 by genotyping chip. Thirty-six pharmacogenetic star allele variants with moderate to strong CPIC therapeutic recommendations were identified in 973 exomes. Exomes had high (98%) genotype concordance with chip-based genotyping. CYP2D6 CNVs were identified in 57/973 exomes. CONCLUSIONS: Exomes outperformed the current chip-based assay in detecting more important pharmacogenetic variant positions and CYP2D6 CNVs for preemptive pharmacogenetic screening. Tools should be developed to derive pharmacogenetic variants from exomes.