Beyond the Single Gene: The Polygenic Architecture of Drug Response

Dear Colleagues,

Overview

For decades, pharmacogenomics has been largely defined by the "one gene, one drug" paradigm, yielding critical insights into individual pharmacokinetic and pharmacodynamic variability. However, it is increasingly evident that drug efficacy and toxicity are rarely monogenic traits. Rather, they are complex phenotypes driven by intricate polygenic architectures, dynamic molecular networks and systemic biomolecular interactions. To truly realize the promise of precision pharmacology, the field must transition from identifying isolated genetic markers to deciphering the profound molecular mechanisms underlying multigenic traits.

This Special Issue, "Beyond the Single Gene: The Polygenic Architecture of Drug Response," aims to capture this critical scientific paradigm shift. We seek to publish groundbreaking research that bridges the gap between polygenic variation and cellular function, shedding light on how complex genetic networks dictate molecular interactions, cellular drug disposition and the etiology of adverse drug reactions.

Aims and Scope

We invite original research articles, comprehensive reviews and forward-looking perspective pieces that dissect the multigenic nature of pharmacological responses at the molecular, cellular and structural levels. We are particularly interested in translational "bedside-to-bench" research that illuminates how network pharmacogenomics alters intracellular signaling, protein–protein interactions and molecular metabolic pathways to drive therapeutic outcomes.

Submissions should align with one or more of the following core themes:

Translational Pharmacogenomics & Molecular Pathogenesis: Studies bridging clinical cohorts and molecular biology. We welcome research translating clinical polygenic discoveries (e.g., GWAS, PGx-PRS) into actionable molecular biomarkers, provided they include functional validation or elucidate the underlying molecular etiology and cellular toxicity of clinical drug responses.

Molecular Mechanisms & Systems Pharmacology: Mapping complex epistasis (gene-gene interactions) and multi-omic networks that govern drug metabolism, transport and target engagement. We welcome mechanistic insights into how polygenic architectures modulate structural conformations, intracellular signalling cascades and downstream transcriptional regulation.

Computational Modelling of Molecular Networks: Development of computational frameworks and application of Artificial Intelligence to untangle the mechanistic pathways underlying Pharmacogenomic Polygenic Risk Scores. Studies using multi-omic integration to predict how polygenic landscapes perturb molecular networks and cellular homeostasis.

Molecular Pathogenesis of Adverse Drug Reactions: Elucidating the molecular basis and cellular toxicity driven by multigenic variations. Translating polygenic discoveries into actionable molecular biomarkers and functional assays demonstrating how cumulative genetic variants disrupt cellular networks to precipitate severe adverse events.

Dr. Leonardo Beltrán-Angarita
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the Special Issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.