Abstract
Despite complex pathways of drug disposition, clinical pharmacogenetic predictors currently rely on only a few high effect variants. Quantification of the polygenic contribution to variability in drug disposition is necessary to prioritize target drugs for pharmacogenomic approaches and guide analytic methods. Dexmedetomidine and fentanyl, often used in postoperative care of pediatric patients, have high rates of inter-individual variability in dosing requirements. Analyzing previously generated population pharmacokinetic parameters, we used Bayesian hierarchical mixed modeling to measure narrow-sense (additive) heritability ( hSNP2 ) of dexmedetomidine and fentanyl clearance in children and identify relative contributions of small, moderate, and large effect-size variants to hSNP2 . We used genome-wide association studies (GWAS) to identify variants contributing to variation in dexmedetomidine and fentanyl clearance, followed by functional analyses to identify associated pathways. For dexmedetomidine, median clearance was 33.0 L/h (interquartile range [IQR] 23.8-47.9 L/h) and hSNP2 was estimated to be 0.35 (90% credible interval 0.00-0.90), with 45% of hSNP2 attributed to large-, 32% to moderate-, and 23% to small-effect variants. The fentanyl cohort had median clearance of 8.2 L/h (IQR 4.7-16.7 L/h), with estimated hSNP2 of 0.30 (90% credible interval 0.00-0.84). Large-effect variants accounted for 30% of hSNP2 , whereas moderate- and small-effect variants accounted for 37% and 33%, respectively. As expected, given small sample sizes, no individual variants or pathways were significantly associated with dexmedetomidine or fentanyl clearance by GWAS. We conclude that clearance of both drugs is highly polygenic, motivating the future use of polygenic risk scores to guide appropriate dosing of dexmedetomidine and fentanyl.