Polygenic risk scores: An overview from bench to bedside for personalised medicine

Abstract

Since the first polygenic risk score (PRS) in 2007, research in this area has progressed significantly. The increasing number of SNPs that have been identified by large scale GWAS analyses has fuelled the development of a myriad of PRSs for a wide variety of diseases and, more recently, to PRSs that potentially identify differential response to specific drugs. PRSs constitute a composite genomic biomarker and potential applications for PRSs in clinical practice encompass risk prediction and disease screening, early diagnosis, prognostication, and drug stratification to improve efficacy or reduce adverse drug reactions. Nevertheless, to our knowledge, no PRSs have yet been adopted into routine clinical practice. Beyond the technical considerations of PRS development, the major challenges that face PRSs include demonstrating clinical utility and circumnavigating the implementation of novel genomic technologies at scale into stretched healthcare systems. In this review, we discuss progress in developing disease susceptibility PRSs across multiple medical specialties, development of pharmacogenomic PRSs, and future directions for the field.

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment

“…Combined, these six variants explained only 3.5% of the variation in platelet function. Regarding warfarin, studies utilizing PRS based on variations in CYP2C9 , VKORC1 and CYP4F2 suggested improved dosing through pharmacogenomic algorithms compared to clinical algorithms and fixed dosing regimens [70]. Additionally, a high PRS for coronary artery disease was associated with an increased risk of recurrent MACE after acute coronary syndrome and exhibited a greater absolute and relative risk reduction with alirocumab treatment [71].…”

Relevance of Pharmacogenomics to the Safe Use of Antimicrobials

“…Many complex traits, including both responses to drugs and susceptibility to adverse drug reactions, are likely to involve contributions from a number of different genetic variants [ 46 , 47 ]. As a result of the considerable progress made in studies involving genome-wide association studies and genome sequencing, a number of polygenic risk scores based on a number of genetic variants have been developed, but very few of these relate to pharmacogenomics [ 47 ]. Though a very promising approach, implementation in routine clinical practice to date is limited.…”

Polygenic risk scores and personalized approaches to cardiometabolic disease prevention and treatment: A short review

“…p-value thresholds, clumping, Bayesian or lasso-based penalization), packages (eg PRScs, LDpred2) and assessment applied can largely affect the end product which may be ultimately differentiated across studies. It is therefore highlighted that standardization of the PRS extraction process 49 is central to facilitating their validation and sequentially increasing their predictive ability. Additionally, in this context, attempts to practically compare PRS results and methodology 4,50-52 can provide useful data for the next steps in the need for a unified, applicable approach to allow for PRSs capable of yielding rapid but reliable results and effective comparisons of findings between populations of different characteristics.…”

“…Although there is a limited number of studies investigating and discussing the extent of PRS effective translation to date, future directions can be encouraging on the incorporation of PRS methodologies in the daily practice [1][2][3] . PRS inclusion in disease screening and the formation of personalized recommendations could potentially offer a solution to the growing pressure applied to healthcare systems for more inclusive strategies and efficient use of financial resources 49 . In the field of nutrigenetics (i.e.…”

“…Understanding the connective links between research conduct and translation is substantial in order to be able to reinforce PRS practical use. An integral part to such an effort would be the effective translational communication between bioinformatics and healthcare sectors in order to enhance proper PRS use and interpretation 49 . Especially when referring to the use of PRSs in cardiometabolic and weight-related disorders, understanding, quantifying and translating the contribution of genetic predisposition is vital in interpreting genetic impact.…”