Identifying rare genetic causes of common diseases can improve diagnostic and treatment strategies, but incurs high costs. We tested whether individuals with common disease and low polygenic risk score (PRS) for that disease generated from less expensive genome-wide genotyping data are more likely to carry rare pathogenic variants.
We identified patients with one of five common complex diseases among 44,550 individuals who underwent exome sequencing in the UK Biobank. We derived PRS for these five diseases, and identified pathogenic rare variant heterozygotes. We tested whether individuals with disease and low PRS were more likely to carry rare pathogenic variants.
While rare pathogenic variants conferred, at most, 5.18-fold (95% confidence interval [CI]: 2.32–10.13) increased odds of disease, a standard deviation increase in PRS, at most, increased the odds of disease by 5.25-fold (95% CI: 5.06–5.45). Among diseased patients, a standard deviation decrease in the PRS was associated with, at most, 2.82-fold (95% CI: 1.14–7.46) increased odds of identifying rare variant heterozygotes.
Rare pathogenic variants were more prevalent among affected patients with a low PRS. Therefore, prioritizing individuals for sequencing who have disease but low PRS may increase the yield of sequencing studies to identify rare variant heterozygotes.
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Genome-wide genotyping data, exome-sequencing data, and phenotypic data from the UK Biobank are available upon successful project application.
Computer codes used to generate the results in this study are available upon reasonable request to the corresponding author.
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This research has been conducted using the UK Biobank Resource under application number 27449. J.B.R.’s research group is supported by the Canadian Institutes of Health Research, the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation of Innovation, and the Fonds de Recherche Québec Santé (FRQS). T.L. is supported by an FRQS Doctoral Training Fellowship and a McGill University Faculty of Medicine Scholarship. J.B.R. is supported by an FRQS Clinical Research Scholarship. These funding agencies had no role in the design, implementation, or interpretation of this study. This study was enabled in part by support provided by Calcul Québec and Compute Canada.
The authors declare no conflicts of interest.
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Lu, T., Zhou, S., Wu, H. et al. Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening. Genet Med (2020). https://doi.org/10.1038/s41436-020-01007-7
- rare variants
- polygenic risk scores
- exome sequencing
- patient prioritization
- risk stratification