Genome-Wide Approach to Measure Variant-Based Heritability of Drug Outcome Phenotypes

Clin Pharmacol Ther. 2021 Sep;110(3):714-722. doi: 10.1002/cpt.2323. Epub 2021 Jul 12.


Pharmacogenomic studies have successfully identified variants-typically with large effect sizes in drug target and metabolism enzymes-that predict drug outcome phenotypes. However, these variants may account for a limited proportion of phenotype variability attributable to the genome. Using genome-wide common variation, we measured the narrow-sense heritability ( h SNP 2 ) of seven pharmacodynamic and five pharmacokinetic phenotypes across three cardiovascular drugs, two antibiotics, and three immunosuppressants. We used a Bayesian hierarchical mixed model, BayesR, to model the distribution of genome-wide variant effect sizes for each drug phenotype as a mixture of four normal distributions of fixed variance (0, 0.01%, 0.1%, and 1% of the total additive genetic variance). This model allowed us to parse h SNP 2 into bins representing contributions of no-effect, small-effect, moderate-effect, and large-effect variants, respectively. For the 12 phenotypes, a median of 969 (range 235-6,304) unique individuals of European ancestry and a median of 1,201,626 (range 777,427-1,514,275) variants were included in our analyses. The number of variants contributing to h SNP 2 ranged from 2,791 to 5,356 (median 3,347). Estimates for h SNP 2 ranged from 0.05 (angiotensin-converting enzyme inhibitor-induced cough) to 0.59 (gentamicin concentration). Small-effect and moderate-effect variants contributed a majority to h SNP 2 for every phenotype (range 61-95%). We conclude that drug outcome phenotypes are highly polygenic. Thus, larger genome-wide association studies of drug phenotypes are needed both to discover novel variants and to determine how genome-wide approaches may improve clinical prediction of drug outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bayes Theorem
  • Female
  • Genetic Variation / genetics*
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Middle Aged
  • Pharmaceutical Preparations / administration & dosage*
  • Pharmacogenomic Testing / methods
  • Phenotype


  • Pharmaceutical Preparations