Clinical use of polygenic risk scores: current status, barriers and future directions

Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

Article  CAS  PubMed  Google Scholar 

Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007). A landmark study in human genetics, demonstrating the power of GWAS by identifying multiple novel genetic variants associated with seven common diseases. The study was an important step forward in understanding the genetic basis of common diseases and led to a subsequent surge in GWAS.

Article  Google Scholar 

Kullo, I. J. et al. Polygenic scores in biomedical research. Nat. Rev. Genet. 23, 524–532 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wray, N. R., Kemper, K. E., Hayes, B. J., Goddard, M. E. & Visscher, P. M. Complex trait prediction from genome data: contrasting EBV in livestock to PRS in humans: genomic prediction. Genetics 211, 1131–1141 (2019). This report provides a framework for understanding the similarities and differences between genomic prediction in livestock and humans. Livestock typically have large family sizes and a greater degree of relatedness within a breed, whereas humans have smaller family sizes and there is a focus on unrelated individuals for genetic analysis.

Article  PubMed  PubMed Central  Google Scholar 

Fisher, R. A. The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52, 339–433 (1918).

Google Scholar 

Hill, W. G. Can more be learned from selection experiments of value in animal breeding programmes? Or is it time for an obituary? J. Anim. Breed. Genet. 128, 87–94 (2011).

Article  CAS  PubMed  Google Scholar 

Okazaki, A., Yamazaki, S., Inoue, I. & Ott, J. Population genetics: past, present, and future. Hum. Genet. 140, 231–240 (2021).

Article  PubMed  Google Scholar 

Donis-Keller, H. et al. A genetic linkage map of the human genome. Cell 51, 319–337 (1987).

Article  CAS  PubMed  Google Scholar 

Kullo, I. J. & Ding, K. Mechanisms of disease: the genetic basis of coronary heart disease. Nat. Clin. Pract. Cardiovasc. Med. 4, 558–569 (2007).

Article  CAS  PubMed  Google Scholar 

Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996). A commentary that was pivotal in shifting the focus from linkage studies to association studies for uncovering the genetics of complex diseases. The authors argued that association studies, given sufficient sample sizes, would have far greater power to detect common variants influencing disease risk, which laid the conceptual groundwork for GWAS.

Article  CAS  PubMed  Google Scholar 

Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590–1605 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wray, N. R., Goddard, M. E. & Visscher, P. M. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 17, 1520–1528 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Choi, S. W., Mak, T. S. & O’Reilly, P. F. Tutorial: a guide to performing polygenic risk score analyses. Nat. Protoc. 15, 2759–2772 (2020). A comprehensive and practical guide for researchers to carry out PRS analyses, offering detailed protocols and best practices.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kachuri, L. et al. Principles and methods for transferring polygenic risk scores across global populations. Nat. Rev. Genet. 25, 8–25 (2024).

Article  CAS  PubMed  Google Scholar 

Boyle, E. A., Li, Y. I. & Pritchard, J. K. An expanded view of complex traits: from polygenic to omnigenic. Cell 169, 1177–1186 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Visscher, P. M., Yengo, L., Cox, N. J. & Wray, N. R. Discovery and implications of polygenicity of common diseases. Science 373, 1468–1473 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adeyemo, A. et al. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps. Nat. Med. 27, 1876–1884 (2021).

Article  Google Scholar 

Craig, J. E. et al. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. Nat. Genet. 52, 160–166 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, J. et al. Polygenic risk score added to conventional case finding to identify undiagnosed chronic obstructive pulmonary disease. JAMA 333, 784–792 (2025).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Linder, J. E. et al. Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing. Am. J. Hum. Genet. 110, 1950–1958 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kullo, I. J. et al. The PRIMED consortium: reducing disparities in polygenic risk assessment. Am. J. Hum. Genet. 111, 2594–2606 (2024). A perspective on the PRIMED consortium, an initiative aimed at improving the accuracy and equity of polygenic risk assessment across diverse populations to address disparities in genomic medicine and make polygenic risk prediction more inclusive and clinically relevant for global populations.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Denny, J. C. et al. The ‘All of Us’ research program. N. Engl. J. Med. 381, 668–676 (2019).

Article  PubMed  Google Scholar 

Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kullo, I. J. Promoting equity in polygenic risk assessment through global collaboration. Nat. Genet. 56, 1780–1787 (2024).

Article  CAS  PubMed  Google Scholar 

Fatumo, S. et al. A roadmap to increase diversity in genomic studies. Nat. Med. 28, 243–250 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wand, H. et al. Improving reporting standards for polygenic scores in risk prediction studies. Nature 591, 211–219 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

O’Sullivan, J. W. et al. Polygenic risk scores for cardiovascular disease: a scientific statement from the American heart association. Circulation 146, e93–e118 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Schunkert, H. et al. Clinical utility and implementation of polygenic risk scores for predicting cardiovascular disease: a clinical consensus statement of the ESC Council on Cardiovascular Genomics, the ESC Cardiovascular Risk Collaboration, and the European Association of Preventive Cardiology. Eur. Heart J. 46, 1372–1383 (2025).

Article  CAS  PubMed  Google Scholar 

Abu-El-Haija, A. 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. 25, 100803 (2023).

Article  CAS  PubMed  Google Scholar 

Majumder, M. A., Guerrini, C. J. & McGuire, A. L. Direct-to-consumer genetic testing: value and risk. Annu. Rev. Med. 72, 151–166 (2021).

Article  CAS 

Comments (0)

No login
gif