| Title: | Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening |
| Journal: | Genetics in Medicine |
| Published: | 28 Oct 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33110269/ |
| DOI: | https://doi.org/10.1038/s41436-020-01007-7 |
| URL: | http://www.gimjournal.org/article/S1098360021049479/pdf |
Publication 5234
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Abstract
PurposeIdentifying 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.MethodsWe 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.ResultsWhile 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.ConclusionRare 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.</p>
6 Authors
- Tianyuan Lu
- Sirui Zhou
- Haoyu Wu
- Vincenzo Forgetta
- Celia M. T. Greenwood
- J. Brent Richards
Enabling scientific discoveries that improve human health