Public health strategies aimed at disease prevention or early detection and intervention have the potential to advance human health worldwide. However, their success depends on the identification of risk factors that underlie disease burden in the general population. Genome-wide association studies (GWAS) have implicated thousands of single-nucleotide polymorphisms (SNPs) in common complex diseases or traits. By calculating a weighted sum of the number of trait-associated alleles harboured by an individual, a polygenic score (PGS), also called a polygenic risk score (PRS), can be constructed that reflects an individual’s estimated genetic predisposition for a given phenotype. Here, we ask six experts to give their opinions on the utility of these probabilistic tools, their strengths and limitations, and the remaining barriers that need to be overcome for their equitable use.
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Acknowledgements
I.J.K. is funded by NIH grants HG-006379, HG-011710 and HL-70710. A.R.M. is supported by funding from the NIH (R00MH117229).
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Iftikhar J. Kullo is a Professor of Cardiovascular Medicine, at Mayo Clinic, Rochester, Minnesota, USA. His research laboratory focuses on the genetic epidemiology of coronary heart disease and implementation of genomic medicine. He is a Principal Investigator in the National Human Genome Research Institute’s eMERGE and PRIMED Networks and serves on the US National Advisory Council on Human Genome Research.
Cathryn M. Lewis is Professor of Genetic Epidemiology and Statistics at King’s College London, UK, where she leads the Social, Genetic and Developmental Psychiatry Centre. She co-chairs the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and leads the Biomarkers and Genomics theme in the NIHR Maudsley Biomedical Research Centre, performing translational research to establish the evidence base for genomics in a clinical setting.
Michael Inouye is a computational biologist who has been analysing human genome data for more than 20 years. He is a Professor and Director of Research at the University of Cambridge, UK, Munz Chair of Cardiovascular Prediction and Prevention at the Baker Heart and Diabetes Institute and Director of the Cambridge Baker Systems Genomics Initiative.
Alicia R. Martin is a population and statistical geneticist. Her research examines the role of human history in shaping global genetic and phenotypic diversity. To ensure that vast Eurocentric study biases do not exacerbate health disparities, she is developing statistical methods, genomics resources and research capacity for diverse and under-represented populations.
Samuli Ripatti is Professor and Vice Director at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, and chair of the Academy of Finland’s Centre of Excellence in Complex Disease Genetics. His research group studies genetic variation and its effects on common disease risks and management. His research uses cardiometabolic diseases and cancers as models to learn about disease mechanisms and genome-based strategies for prevention and prognosis.
Nilanjan Chatterjee is a Bloomberg Distinguished Professor at Johns Hopkins University, USA, and was previously the Chief of the Biostatistics Branch at the National Cancer Institute. He is known for his research on sample size requirements for polygenic prediction, methods for building polygenic scores (PGS) and integration of PGS with non-genetic risk factors.
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C.M.L. is a member of the Scientific Advisory Board for Myriad Neuroscience. A.R.M. has consulted for 23andMe and Illumina and received speaker fees from Genentech, Pfizer and Illumina. The other contributors declare no competing interests.
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Related links
Clinical Genome Resource (ClinGen) Complex Disease Working Group: https://www.clinicalgenome.org/working-groups/complex-disease/
eMERGE Network: https://emerge-network.org/
Global Biobank Meta-analysis Initiative: www.globalbiobankmeta.org
International Consortium for Integrative Genomics Prediction: www.interveneproject.eu
Polygenic Score Catalogue: https://www.pgscatalog.org/
PRIMED consortium: https://primedconsortium.org/
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Kullo, I.J., Lewis, C.M., Inouye, M. et al. Polygenic scores in biomedical research. Nat Rev Genet 23, 524–532 (2022). https://doi.org/10.1038/s41576-022-00470-z
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DOI: https://doi.org/10.1038/s41576-022-00470-z
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