Genomewide Association Studies in Pharmacogenomics

Abstract

The increasing availability of genotype data linked with information about drug-response phenotypes has enabled genome-wide association studies (GWAS) that uncover genetic determinants of drug response. GWAS have discovered associations between genetic variants and both drug efficacy and adverse drug reactions. Despite these successes, the design of GWAS in pharmacogenomics faces unique challenges. In this review we analyze the last decade of GWAS in pharmacogenomics. We review trends in publications over time, including the drugs and drug classes studied and the clinical phenotypes used. Several data sharing consortia have contributed substantially to the PGx GWAS literature. We anticipate increased focus on biobanks and highlight phenotypes that would best enable future pharmacogenomics discoveries.

AWOT and CWOT for genotype and genotype-by-treatment interaction joint analysis in pharmacogenetics GWAS

“…To date, many associations between genetic variation and inter-individual difference in drug response have been discovered to tailor treatments to the genetic makeup of the patient for patient stratification and therapeutic value propositions ( Nelson et al , 2016 ). However, PGx GWAS face unique challenges including small sample size, limited global representation and traditional statistical tests with low power ( Bienfait et al , 2022 ; McInnes et al , 2021 ). To detect genetic biomarkers that can explain more (unexplained) heritability in drug response, the field needs larger sample sizes, more diverse cohorts and a broader array of statistical tests ( McInnes et al , 2021 ).…”

“…Genome-wide association studies (GWAS) provide a hypothesis free approach for identifying associations between genotype and phenotype. To date, GWAS have identified many genetic markers associated with complex diseases and drug responses ( Giacomini et al , 2017 ; McInnes et al , 2021 ). Pharmacogenomics (PGx) is an important tool for precision medicine, studying how pharmacokinetics, pharmacodynamics, efficacy and safety responses to drugs are associated with genetic information at the molecular level of treated subjects ( Chen et al , 2013 ; Roden et al , 2019 ).…”

“…Pharmacogenomics (PGx) is an important tool for precision medicine, studying how pharmacokinetics, pharmacodynamics, efficacy and safety responses to drugs are associated with genetic information at the molecular level of treated subjects ( Chen et al , 2013 ; Roden et al , 2019 ). PGx GWAS have been widely used to identify genetic biomarkers associated with drug response and further understand the underly mechanisms of the inter-individual difference in drug responses ( Giacomini et al , 2017 ; McInnes et al , 2021 ).…”

A Systematic Review and Analysis of the Use of Polygenic Scores in Pharmacogenomics

“…While genome-wide association studies (GWASs) have been successful in identifying genetic variants that are associated with drug treatment responses, in many cases, the effects of individual genetic variants are small. 21 Therefore, individually, these genetic variants are limited in their ability to provide clinically meaningful predictions of treatment outcomes. The inclusion of PGSs into prediction algorithms may aid in improving the accuracy of these predictions.…”

“…The inclusion of PGSs into prediction algorithms may aid in improving the accuracy of these predictions. However, while the use of GWASs in pharmacogenomics has recently been reviewed, 21 to the best of our knowledge, there are currently no publications which have reviewed the evidence available for the use of PGSs in the context of pharmacogenomics as a whole.…”