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Prioritising individuals with disease but low PRS for sequencing

A recent study, published in Genetics in Medicine, has found that prioritising individuals for sequencing who have disease but low polygenic risk score (PRS), may help identify rare variant heterozygotes.

Common disease

Most common diseases are partially heritable. However, they can sometimes be caused by rare pathogenic variants. The identification of these rare variants can sometimes alter clinical care through tailoring diagnostic and/or treatment strategies. Unlike in rare diseases, experts do not routinely look for rare variants in common diseases. This is often because targeted sequencing panels or exome sequencing are required. These costly technologies generally have low yield due to the rarity of actionable genetic variants. Therefore, ways to efficiently identify individuals with common diseases but rare actionable variants could help improve clinical care.

A suggested approach is the use of PRS. Heritable predisposition to any disease could arise through many common genetic variants with small effect (captured by PRS) or rare variants of large effect. Therefore, individuals with a disease but low polygenic predisposition may be more likely to harbour a rare genetic variant. PRS generally does not capture rare genetic variants. As a result, this score is likely to be independent of rare variant heterozygous status.


In this study, researchers tested the hypothesis that individuals with a low PRS for common disease are more likely to harbour rare genetic variants than individuals without a low score. To achieve this, the team generated PRS for five complex diseases. These included breast cancer, colorectal cancer, type 2 diabetes, osteoporosis and short stature. They then assessed the frequency of rare causal genetic variants among 44,550 individuals. Specifically, individuals with exome sequencing data from the UK Biobank.

They found that among patients with disease, a standard deviation decrease in the PRS associated with a 2.82-fold increased odds of identifying rare variant heterozygotes. In other words, among patients for five common diseases those with a low PRS had a higher likelihood of being heterozygotes of rare pathogenic variants. These findings suggest that PRS may help in prioritising patients who should undergo genetic testing for known disease-causing genes. Therefore, the yield of clinical sequencing studies to identify rare pathogenic variants could be increased by stratifying patients with disease, based on their polygenic score.

Image credit: By kjpargeter –