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The personal and clinical utility of polygenic risk scores

Abstract

Initial expectations for genome-wide association studies were high, as such studies promised to rapidly transform personalized medicine with individualized disease risk predictions, prevention strategies and treatments. Early findings, however, revealed a more complex genetic architecture than was anticipated for most common diseases — complexity that seemed to limit the immediate utility of these findings. As a result, the practice of utilizing the DNA of an individual to predict disease has been judged to provide little to no useful information. Nevertheless, recent efforts have begun to demonstrate the utility of polygenic risk profiling to identify groups of individuals who could benefit from the knowledge of their probabilistic susceptibility to disease. In this context, we review the evidence supporting the personal and clinical utility of polygenic risk profiling.

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Fig. 1: Contrasting and combining clinical risk factors and polygenic risk.
Fig. 2: Contrasting risk stratification versus risk prediction.
Fig. 3: Risks and benefits by polygenic risk score tier.

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Acknowledgements

This work is supported by The Scripps Translational Science, a National Institutes of Health-National Center for Advancing Translational Sciences (NIH-NCATS) Clinical and Translational Science Award (CTSA; 5 UL1 TR001114). Further support is from U54GM114833 and the Foundation Leducq.

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Nature Reviews Genetics thanks N. Chatterjee, P. Kraft and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Polygenic risk scores

(PRSs). A weighted sum of the number of risk alleles carried by an individual, where the risk alleles and their weights are defined by the loci and their measured effects as detected by genome wide association studies.

Genetic architecture

The underlying genetic basis of a trait or disease. The combination of the number, type, frequency, relationship between and magnitude of effect of genetic variants contributing to a trait.

Heritability

The proportion of total variation between individuals within a population that is due to genetic factors.

Genome-wide association studies

(GWAS). A genetic study designed to rapidly scan for statistical links between a genome-wide set of known genetic variants and a disease or other phenotype of interest.

Alleles

One of two or more alternative forms of a genetic variation.

Absolute risk

Absolute risk is the unqualified probability, or risk, that a certain event will occur; it ranges from 0–100%.

Monogenic

A term used to describe diseases with one contributing gene, that is, familial risk is driven by high-risk variants, which is in contrast to polygenic disease, where several genetic factors contribute to the disease.

Minor allele frequency

(MAF). The frequency at which the second most frequent allele occurs in a population.

Imputation

A technique for the inference of unobserved genotypes based on their statistical relationship with observed genotypes.

Relative risk

Relative risk is the probability, or risk, that a certain event will occur in comparison to the event rate in a reference group; often expressed as the ratio of absolute risk between two groups, thus a value of 1.0 means no difference in risk.

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Torkamani, A., Wineinger, N.E. & Topol, E.J. The personal and clinical utility of polygenic risk scores. Nat Rev Genet 19, 581–590 (2018). https://doi.org/10.1038/s41576-018-0018-x

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