Tianyuan Lu1,2, Sirui Zhou1, Haoyu Wu1,3, Vincenzo Forgetta1, Celia M T Greenwood1,3,4,5, J Brent Richards6,7,8,9. 1. Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. 2. Quantitative Life Sciences Program, McGill University, Montreal, QC, Canada. 3. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada. 4. Department of Human Genetics, McGill University, Montreal, QC, Canada. 5. Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada. 6. Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. brent.richards@mcgill.ca. 7. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada. brent.richards@mcgill.ca. 8. Department of Human Genetics, McGill University, Montreal, QC, Canada. brent.richards@mcgill.ca. 9. Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. brent.richards@mcgill.ca.
Abstract
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.
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.
Authors: Tianyuan Lu; Vincenzo Forgetta; Haoyu Wu; John R B Perry; Ken K Ong; Celia M T Greenwood; Nicholas J Timpson; Despoina Manousaki; J Brent Richards Journal: J Clin Endocrinol Metab Date: 2021-06-16 Impact factor: 6.134
Authors: Burcu F Darst; Xin Sheng; Rosalind A Eeles; Zsofia Kote-Jarai; David V Conti; Christopher A Haiman Journal: Eur Urol Date: 2021-05-01 Impact factor: 24.267
Authors: Dan Zhou; Dongmei Yu; Jeremiah M Scharf; Carol A Mathews; Lauren McGrath; Edwin Cook; S Hong Lee; Lea K Davis; Eric R Gamazon Journal: Nat Commun Date: 2021-07-20 Impact factor: 14.919