Journal
GENETICS IN MEDICINE
Volume 23, Issue 3, Pages 508-515Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-01007-7
Keywords
rare variants; polygenic risk scores; exome sequencing; patient prioritization; risk stratification
Categories
Funding
- Canadian Institutes of Health Research
- Lady Davis Institute of the Jewish General Hospital
- Canadian Foundation of Innovation
- Fonds de Recherche Quebec Sante (FRQS)
- FRQS Doctoral Training Fellowship
- McGill University Faculty of Medicine Scholarship
- FRQS Clinical Research Scholarship
- Calcul Quebec
- Compute Canada
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Rare pathogenic variants are more prevalent among affected patients with a low PRS. Therefore, prioritizing individuals with disease but low PRS for sequencing may increase the yield of sequencing studies to identify rare variant heterozygotes.
Purpose 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. Methods 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. Results 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. Conclusion 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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