Genome-wide associations spanning 194 in-hospital drug dosage change phenotypes highlight diverse genetic backgrounds in concurrent drug therapy

As populations get older and medicine consumption rises, the rate of concurrent drug use and polypharmacy among patients is increasing. Polypharmacy is known to complicate therapy and increase the risk of drug-drug interactions, the individuality of which remain largely unexplored. Here, we perform a series of genome-wide association studies to identify variants associated with dosage changes during episodes of concurrent drug therapy. We extracted in-hospital drug prescription records from 847,537 patients in a population-wide Danish hospital cohort. Using imputed genotype data from the Copenhagen Hospital Biobank and the Danish Blood Donor Study we then performed a series of genome-wide association analyses across 194 drug pair phenotypes fulfilling selection criteria. We identified 51 genome-wide significant (p < 5E-08) loci, 49 so far unreported in any genome-wide association studies, associated with dosage changes across 42 different drug pair phenotypes. 49 of the identified loci were unique to the respective drug pairs. Through annotation of the identified loci, expression quantitative trait loci analyses, and gene-based tests we found links to 57 distinct genes, several of which have previously been associated with disease. This study identifies genes that may modulate response to drug therapy in the context of polypharmacy. Our findings reveal distinct patterns of genetic variation across different drug pairs, suggesting a diverse set of genes involved in drug efficacy and drug response. This study may give a better understanding of the individuality of such mechanisms and may aid the development personalized treatment approaches.

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Publication Details

Journal
Computational and Structural Biotechnology Journal
Published
2025-01-01
DOI
https://doi.org/10.1016/j.csbj.2025.06.042
Primary Topic
Pharmacogenetics and Drug Metabolism
Type
article
Field-Weighted Citation Impact
0.00

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article

Genome-wide associations spanning 194 in-hospital drug dosage change phenotypes highlight diverse genetic backgrounds in concurrent drug therapy

Mie Topholm Bruun, Gianluca Mazzoni, Jorge Hernansanz Biel, Alexander Pil Henriksen et al.
Computational and Structural Biotechnology Journal
Pharmacogenetics and Drug Metabolism
article

Genome-wide associations spanning 194 in-hospital drug dosage change phenotypes highlight diverse genetic backgrounds in concurrent drug therapy

Mie Topholm Bruun, Gianluca Mazzoni, Jorge Hernansanz Biel, Alexander Pil Henriksen, Christina Mikkelsen, Thomas Folkmann Hansen, Søren Brunak, Henrik Ullum, Erik Sørensen, Liam Quinn, Henrik Hjalgrim, Amalie Dahl Haue, Michael Schwinn, Henning Bundgaard, Ole Birger Pedersen, Sisse Rye Ostrowski, Ewan Birney, Karina Banasik, Hannah Currant, Khoa Manh Dinh, Christian Erikstrup, María Herrero-Zazo, Ioannis Louloudis, Cristina Leal Rodríguez
article en

Abstract

As populations get older and medicine consumption rises, the rate of concurrent drug use and polypharmacy among patients is increasing. Polypharmacy is known to complicate therapy and increase the risk of drug-drug interactions, the individuality of which remain largely unexplored. Here, we perform a series of genome-wide association studies to identify variants associated with dosage changes during episodes of concurrent drug therapy. We extracted in-hospital drug prescription records from 847,537 patients in a population-wide Danish hospital cohort. Using imputed genotype data from the Copenhagen Hospital Biobank and the Danish Blood Donor Study we then performed a series of genome-wide association analyses across 194 drug pair phenotypes fulfilling selection criteria. We identified 51 genome-wide significant (p < 5E-08) loci, 49 so far unreported in any genome-wide association studies, associated with dosage changes across 42 different drug pair phenotypes. 49 of the identified loci were unique to the respective drug pairs. Through annotation of the identified loci, expression quantitative trait loci analyses, and gene-based tests we found links to 57 distinct genes, several of which have previously been associated with disease. This study identifies genes that may modulate response to drug therapy in the context of polypharmacy. Our findings reveal distinct patterns of genetic variation across different drug pairs, suggesting a diverse set of genes involved in drug efficacy and drug response. This study may give a better understanding of the individuality of such mechanisms and may aid the development personalized treatment approaches.

Computational and Structural Biotechnology JournalVol. 28
Statens Serum Institut (DK), University of Copenhagen (DK), European Bioinformatics Institute (GB), Aarhus University (DK), Novo Nordisk Foundation (DK), Odense University Hospital (DK), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Gentofte Hospital (DK), Rigshospitalet (DK), University of Oxford (GB), Nuffield Health (GB), Copenhagen Prospective Studies on Asthma in Childhood (DK), Danish Cancer Society (DK), Zealand University Hospital Køge (DK)
Eli Lilly and Company, Innovationsfonden, Novo Nordisk, Novo Nordisk Fonden, H. Lundbeck A/S
Openalex Percentile: Top 80%
Pharmacogenetics and Drug Metabolism
DOIOpen Access PDFOpenAlex
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