Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening
Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening
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DOI：
10.1038/s41436-020-01007-7
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发表时间：
2020-10-28
影响因子：
8.8
通讯作者：
Richards, J. Brent
中科院分区：
文献类型：
--
作者：
Lu, Tianyuan;Zhou, Sirui;Richards, J. Brent
目的确定常见疾病的罕见遗传原因可以改善诊断和治疗策略，但会产生高昂的费用。我们测试了患有常见疾病和低多基因风险评分（PRS）的个体是否更有可能携带罕见的致病变异，这些多基因风险评分（PRS）来自较便宜的全基因组基因分型数据。方法：在英国生物银行进行外显子组测序的44,550名患者中，我们确定了患有五种常见复杂疾病之一的患者。我们得到了这五种疾病的PRS，并鉴定了致病的罕见变异杂合子。我们测试了患有疾病和低PRS的个体是否更有可能携带罕见的致病变异。结果虽然罕见的致病变异最多使患病几率增加5.18倍（95%可信区间[CI]: 2.32-10.13），但PRS的标准偏差增加最多使患病几率增加5.25倍（95% CI: 5.06-5.45）。在患病患者中，PRS的标准差降低最多与2.82倍（95% CI: 1.14-7.46）的发现罕见变异杂合子的几率增加相关。结论低PRS患者多为罕见致病性变异。因此，优先考虑有疾病但PRS低的个体进行测序可能会增加测序研究的产量，以鉴定罕见的变异杂合子。
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.