The Polygenic Risk Score in Clinical Pharmacy: From Genomic Architecture to Precision Drug Therapy: A Narrative Review

Abstract

Background: Precision medicine increasingly relies on polygenic risk scores (PRS) to predict drug efficacy, safety, and therapeutic variability. Traditional monogenic pharmacogenetics, focused on individual gene variants, explains only 20-40% of drug response variation, leaving substantial "missing heritability." Polygenic models aggregating thousands of genome-wide variants offer improved prediction, yet clinical implementation in pharmacy practice remains inconsistent and incomplete. Objective: This narrative review synthesizes evidence on PRS methodologies, clinical applications across therapeutic domains, the pharmacist's role in precision drug therapy, barriers to adoption, and emerging technologies, to provide a comprehensive synthesis for pharmacy educators, practitioners, and health system leaders. Methods: A targeted literature search of PubMed, Google Scholar, and bioRxiv (2010-2025) identified 90 peer-reviewed articles addressing PRS genomic principles, calculation and validation methodologies, clinical applications in cardiovascular (statins, clopidogrel), psychiatric (antidepressants, antipsychotics), and endocrine (metformin) pharmacotherapy, pharmacy implementation frameworks, and ethical and regulatory considerations. Articles were selected based on methodological rigor, applicability to clinical pharmacy practice, and contribution to understanding of PRS mechanisms, validation, or implementation. Results: Polygenic models capture cumulative genetic burden and demonstrate moderate to good predictive accuracy across therapeutic domains (AUC 0.60-0.75), exceeding monogenic approaches. Clinical applications are emerging but largely research-stage; few pragmatic trials assess PRS-guided pharmacotherapy effectiveness versus standard care. Pharmacists' competencies as genomic consultants are well-articulated conceptually but underdeveloped operationally. Major barriers include economic constraints (cost of testing, lack of reimbursement), educational gaps (insufficient pharmacist training), methodological concerns (ancestry bias, limited population-specific models), and incomplete regulatory frameworks and implementation infrastructure. Literature distribution shows emphasis on clinical applications (31%) and PRS methodology (24%), with limited evidence on pharmacy implementation (20%) or health economic impact. Conclusion: PRS represent a paradigm shift toward precision pharmacotherapy but require systematic workforce development, health system investment, policy reform, and implementation science evidence to realize clinical and equitable impact