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Sadowski, M.* ; Thompson, M.* ; Mefford, J.* ; Haldar, T.* ; Oni-Orisan, A.* ; Border, R.* ; Pazokitoroudi, A.* ; Cai, N. ; Ayroles, J.F.* ; Sankararaman, S.* ; Dahl, A.W.* ; Zaitlen, N.*

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

Cell Genom. 4:100722 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene-environment Interactions ; Genetic Heterogeneity ; Genetic Testing ; Heritability ; Heteroskedasticity ; Personalized Medicine ; Pharmacogenomics; Genome-wide Association; Environment Interactions; Cardiovascular-disease; Polygenic-score; Uk Biobank; Metformin; Therapy; Risk; Efficacy; Genotype
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 2666-979X
e-ISSN 2666-979X
Journal Cell Genomics
Quellenangaben Volume: 4, Issue: 12, Pages: , Article Number: 100722 Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Pioneer Campus
PSP Element(s) G-510007-001
Grants National Institutes of Health
Chan Zuckerberg Initiative grant
DOI 10.1016/j.xgen.2024.100722
WOS ID 001385667700001
Scopus ID 85211336905
PubMed ID 39637863
Erfassungsdatum 2024-12-10
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