Characterizing the genetic architecture of drug response using gene-context interaction methods

• DOI: 10.1016/j.xgen.2024.100722
• Publication Date: 2024-12-04T15:38:32Z
• Authors: Michal Sadowski; Mike Thompson; Joel Mefford; Tanushree Haldar; Akinyemi Oni-Orisan; Richard Border; Ali Pazokitoroudi; Na Cai; Julien F. Ayroles; Sriram Sankararaman; Andy W. Dahl; Noah Zaitlen
• Keywords: Male; Blood Glucose; Multifactorial Inheritance; 610; heritability; Article; LDL; genetic testing; genetic heterogeneity; 616; Genetics; Humans; Precision Medicine; Retrospective Studies; Glycated Hemoglobin; pharmacogenomics; Biomedical and Clinical Sciences; Human Genome; Genetic Variation; Pharmacology and Pharmaceutical Sciences; gene-environment interactions; personalized medicine; Biological Sciences; Metformin; Good Health and Well Being; Methotrexate; Cholesterol; Pharmacogenetics; 6.1 Pharmaceuticals; Female; Patient Safety; Warfarin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; heteroskedasticity

Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank. We find that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as their side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). We identify dozens of genes that modify drug response, which we replicate in a retrospective pharmacogenomic study. Finally, we find that polygenic score (PGS) accuracy varies up to 2-fold depending on treatment status, showing that standard PGSs are likely to underperform in clinical contexts.