Assessing the capability of massively parallel sequencing for opportunistic pharmacogenetic screening

Abstract

PurposeTo 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.MethodsWe 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.ResultsFor 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.ConclusionsExomes 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.