Genome‐Wide Approach to Measure Variant‐Based Heritability of Drug Outcome Phenotypes
Year: 2021
Type: article
Study design: Observational Study
Abstract: 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 ( ) 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 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 ranged from 2,791 to 5,356 (median 3,347). Estimates for 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 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.
DOI: 10.1002/cpt.2323
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: Pharmacogenomics of Arrhythmia Therapy, EMR Phenotypes and Community Engaged Genomic Associations, PAAR4Kids-Pharmacogenomics of Anticancer Agents Research in Children, Pharmacogenomics of Anti-platlet Intervention-2 (PAPI-2) Study, Children's Oncology Group Statistics and Data Center Grant, Pharmacogenomics of Tacrolimus and New Onset Diabetes After Kidney Transplant, PharmGKB: pharmacogenomics knowledge for precision medicine, Alzheimer's Disease Patient Registry (ADPR/ACT), Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), Medical Scientist Training Program, Genomic Approaches for Predicting Drug Response, Northwestern Genomic Risk Assessment and Management Program, Genome-wide Studies from the NUgene Biorespository, Genome-Wide Study of Cataract and Low HDL in the Personalized Medicine Research P, Genetic Determinants of Weight Loss and Resolution of Co-Morbidities, Institutional Clinical and Translational Science Award, Genetic Discovery and Application in a Clinical Setting Continuing a Partnership, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, Mid-Atlantic Nutrition Obesity Research Center, Geisinger eGenonic Medicine (GeM) Program, Vanderbilt Genome-Electronic Records Project, The Vanderbilt Institute for Clinical and Translational Research (VICTR), PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), Genetic determinants of NAFLD severity and progression, IRIS: Incorporating Research Into Sight, University of Wisconsin Institute for Clinical and Translational Research, PharmGKB, Cancer Center Support Grant (CCSG), Medical Scientist Training Program
OpenAlex ID: W3173698406