SMART-Topic: Polygenic Risk Score (PRS): Development, Interpretation and Utility
DOI:
https://doi.org/10.69734/sqe1mp91Keywords:
genetic, polygenic risk score, celiac disease, type 1 diabetes, type 2 diabetes, hypertriglyceridemia, gallstones, pancreatic ductal adenocarcinoma, complex trait genetics, GWAS, SNVAbstract
Polygenic Risk Scores (PRS) use dozens to hundreds of genetic variants from disease populations to add insights to an individual’s risk of that disease. Many PRSs are undergoing clinical trials to assess their ability to enhance clinical risk assessments, making the assessments more personal and accurate while enabling earlier implementation of disease mitigation strategies.(3-7) This paper focuses on the development, utility, interpretation, and limitations of PRS in clinical practice. A PRS is the weighted sum of disease risk contributed by multiple, common, single nucleotide variants (SNVs) across the genome. PRSs are developed using output from one or more genome-wide association studies (GWAS) and are effective for both binary and continuous traits. The accuracy and utility of a PRS depend on the SNVs used in the GWAS, the selection of SNVs for the PRS, the population tested, the characteristics of the disorder, and the accuracy of phenotyping. Interpretation must be done in the context of overall patient risk, such as age, sex, ancestry, past medical history, family history, lifestyle, and biomarkers. Better tools are needed for translation of PRS into the clinical practice of healthcare professionals
References
Lim J, Wirth J, Wu K, Giovannucci E, Kraft P, Turman C, et al. Obesity, Adiposity, and Risk of Symptomatic Gallstone Disease According to Genetic Susceptibility. Clin Gastroenterol Hepatol. 2022;20(5):e1083-e120 D.O.I: 10.1016/j.cgh.2021.06.044. PMID: 34217876
Tanigawa Y, Qian J, Venkataraman G, Justesen JM, Li R, Tibshirani R, et al. Significant sparse polygenic risk scores across 813 traits in UK Biobank. PLoS Genet. 2022;18(3):e1010105 D.O.I: 10.1371/journal.pgen.1010105. PMID: 35324888
Pastorino R, Pezzullo AM, Agodi A, de Waure C, Mazzucco W, Russo L, et al. Efficacy of polygenic risk scores and digital technologies for INNOvative personalized cardiovascular disease PREVention in high-risk adults: protocol of a randomized controlled trial. Front Public Health. 2024;12:1335894 D.O.I: 10.3389/fpubh.2024.1335894. PMID: 38947346
Vassy JL, Brunette CA, Lebo MS, MacIsaac K, Yi T, Danowski ME, et al. The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care. Am J Hum Genet. 2023;110(11):1841-52 D.O.I: 10.1016/j.ajhg.2023.10.001. PMID: 37922883
Naderian M, Hamed ME, Vaseem AA, Norland K, Dikilitas O, Teymourzadeh A, et al. Effect of Disclosing a Polygenic Risk Score for Coronary Heart Disease on Adverse Cardiovascular Events. Circ Genom Precis Med. 2025;18(2):e004968 D.O.I: 10.1161/CIRCGEN.124.004968. PMID: 40151934
Kullo IJ, Jouni H, Austin EE, Brown SA, Kruisselbrink TM, Isseh IN, et al. Incorporating a Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial). Circulation. 2016;133(12):1181-8 D.O.I: 10.1161/CIRCULATIONAHA.115.020109. PMID: 26915630
Christensen KD, Schonman EF, Robinson JO, Roberts JS, Diamond PM, Lee KB, et al. Behavioral and psychological impact of genome sequencing: a pilot randomized trial of primary care and cardiology patients. NPJ Genom Med. 2021;6(1):72 D.O.I: 10.1038/s41525-021-00236-2. PMID: 34429410
Ge T, Irvin MR, Patki A, Srinivasasainagendra V, Lin YF, Tiwari HK, et al. Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations. Genome medicine. 2022;14(1):70 D.O.I: 10.1186/s13073-022-01074-2. PMID: 35765100
Johnson L, Zhu J, Scott ER, Wineinger NE. An Examination of the Relationship between Lipid Levels and Associated Genetic Markers across Racial/Ethnic Populations in the Multi-Ethnic Study of Atherosclerosis. PLoS One. 2015;10(5):e0126361 D.O.I: 10.1371/journal.pone.0126361. PMID: 25951326
Lee A, Mavaddat N, Wilcox AN, Cunningham AP, Carver T, Hartley S, et al. BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genet Med. 2019;21(8):1708-18 D.O.I: 10.1038/s41436-018-0406-9. PMID: 30643217
Ficorella L, Yang X, Mavaddat N, Carver T, Hassan H, Dennis J, et al. Adapting the BOADICEA breast and ovarian cancer risk models for the ethnically diverse UK population. Br J Cancer. 2025 D.O.I: 10.1038/s41416-025-03117-y. PMID: 40676226
Mavaddat N, Pharoah PD, Michailidou K, Tyrer J, Brook MN, Bolla MK, et al. Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst. 2015;107(5) D.O.I: 10.1093/jnci/djv036. PMID: 25855707
Sharma S, Tapper WJ, Collins A, Hamady ZZR. Predicting Pancreatic Cancer in the UK Biobank Cohort Using Polygenic Risk Scores and Diabetes Mellitus. Gastroenterology. 2022;162(6):1665-74 e2 D.O.I: 10.1053/j.gastro.2022.01.016. PMID: 35065983
Sharp SA, Jones SE, Kimmitt RA, Weedon MN, Halpin AM, Wood AR, et al. A single nucleotide polymorphism genetic risk score to aid diagnosis of coeliac disease: a pilot study in clinical care. Aliment Pharmacol Ther. 2020;52(7):1165-73 D.O.I: 10.1111/apt.15826. PMID: 32790217
Khan A, Shang N, Nestor JG, Weng C, Hripcsak G, Harris PC, et al. Polygenic risk alters the penetrance of monogenic kidney disease. Nature communications. 2023;14(1):8318 D.O.I: 10.1038/s41467-023-43878-9. PMID: 38097619
Mars N, Koskela JT, Ripatti P, Kiiskinen TTJ, Havulinna AS, Lindbohm JV, et al. Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers. Nat Med. 2020;26(4):549-57 D.O.I: 10.1038/s41591-020-0800-0. PMID: 32273609
Fahed AC, Wang M, Homburger JR, Patel AP, Bick AG, Neben CL, et al. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. Nature communications. 2020;11(1):3635 D.O.I: 10.1038/s41467-020-17374-3. PMID: 32820175
Lazarte J, Dron JS, McIntyre AD, Skanes AC, Gula LJ, Tang AS, et al. Role of Common Genetic Variation in Lone Atrial Fibrillation. Circ Genom Precis Med. 2021;14(1):e003179 D.O.I: 10.1161/CIRCGEN.120.003179. PMID: 33517663
Mars N, Lindbohm JV, Della Briotta Parolo P, Widen E, Kaprio J, Palotie A, et al. Systematic comparison of family history and polygenic risk across 24 common diseases. Am J Hum Genet. 2022;109(12):2152-62 D.O.I: 10.1016/j.ajhg.2022.10.009. PMID: 36347255
Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature. 2024;627(8003):347-57 D.O.I: 10.1038/s41586-024-07019-6. PMID: 38374256
Forrest IS, Chaudhary K, Paranjpe I, Vy HMT, Marquez-Luna C, Rocheleau G, et al. Genome-wide polygenic risk score for retinopathy of type 2 diabetes. Hum Mol Genet. 2021;30(10):952-60 D.O.I: 10.1093/hmg/ddab067. PMID: 33704450
Yao Z, Zhang X, Deng L, Zhang J, Wen Y, Zheng D, et al. Exploring the Genetic Relationship Between Type 2 Diabetes and Cardiovascular Disease: A Large-Scale Genetic Association and Polygenic Risk Score Study. Biomolecules. 2024;14(11) D.O.I: 10.3390/biom14111467. PMID: 39595643
Yu G, Tam CHT, Lim CKP, Shi M, Lau ESH, Ozaki R, et al. Type 2 diabetes pathway-specific polygenic risk scores elucidate heterogeneity in clinical presentation, disease progression and diabetic complications in 18,217 Chinese individuals with type 2 diabetes. Diabetologia. 2025;68(3):602-14 D.O.I: 10.1007/s00125-024-06309-y. PMID: 39531041
Singh O, Verma M, Dahiya N, Senapati S, Kakkar R, Kalra S. Integrating Polygenic Risk Scores (PRS) for Personalized Diabetes Care: Advancing Clinical Practice with Tailored Pharmacological Approaches. Diabetes Ther. 2025;16(2):149-68 D.O.I: 10.1007/s13300-024-01676-6. PMID: 39688777
van Heel DA, West J. Recent advances in coeliac disease. Gut. 2006;55(7):1037-46 D.O.I: 10.1136/gut.2005.075119. PMID: 16766754
Abraham G, Rohmer A, Tye-Din JA, Inouye M. Genomic prediction of celiac disease targeting HLA-positive individuals. Genome medicine. 2015;7(1):72 D.O.I: 10.1186/s13073-015-0196-5. PMID: 26244058
Plym A, Zhang Y, Stopsack KH, Ugalde-Morales E, Seibert TM, Conti DV, et al. Early Prostate Cancer Deaths Among Men With Higher vs Lower Genetic Risk. JAMA Netw Open. 2024;7(7):e2420034 D.O.I: 10.1001/jamanetworkopen.2024.20034. PMID: 38958976
Tran SD, Pillemer SR, Dutra A, Barrett AJ, Brownstein MJ, Key S, et al. Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study. Lancet. 2003;361(9363):1084-8 D.O.I: 10.1016/S0140-6736(03)12894-2. PMID: 12672312
DiGuardo MA, Kester SJ, Mahaffey VJ, Hammel SA, Heaser KK, Hofich CD, et al. Does Transfusion of Red Blood Cells Impact Germline Genetic Test Results? J Pers Med. 2020;10(4) D.O.I: 10.3390/jpm10040268. PMID: 33316904
van den Boogaard WMC, Komninos DSJ, Vermeij WP. Chemotherapy Side-Effects: Not All DNA Damage Is Equal. Cancers (Basel). 2022;14(3) D.O.I: 10.3390/cancers14030627. PMID: 35158895
Polygenic Risk Score Task Force of the International Common Disease A. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps. Nat Med. 2021;27(11):1876-84 D.O.I: 10.1038/s41591-021-01549-6. PMID: 34782789
Zhai S, Zhang H, Mehrotra DV, Shen J. Pharmacogenomics polygenic risk score for drug response prediction using PRS-PGx methods. Nature communications. 2022;13(1):5278 D.O.I: 10.1038/s41467-022-32407-9. PMID: 36075892
O'Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, Damrauer SM, Ashley EA, et al. Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2022;146(8):e93-e118 D.O.I: 10.1161/CIR.0000000000001077. PMID: 35862132
Abu-El-Haija A, Reddi HV, Wand H, Rose NC, Mori M, Qian E, et al. The clinical application of polygenic risk scores: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(5):100803 D.O.I: 10.1016/j.gim.2023.100803. PMID: 36920474
Reddi HV, Wand H, Funke B, Zimmermann MT, Lebo MS, Qian E, et al. Laboratory perspectives in the development of polygenic risk scores for disease: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(5):100804 D.O.I: 10.1016/j.gim.2023.100804. PMID: 36971772
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