Summarizing polygenic risks for complex diseases in a clinical whole-genome report.
Summarizing polygenic risks for complex diseases in a clinical whole-genome report.
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DOI：
10.1038/gim.2014.143
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
MedSeq Project
中科院分区：
文献类型：
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作者：
Kong SW;Lee IH;Leshchiner I;Krier J;Kraft P;Rehm HL;Green RC;Kohane IS;MacRae CA;MedSeq Project
致病突变和药物基因组变异是临床全基因组测序的主要兴趣。然而，使用已建立的风险等位基因估计常见复杂疾病的遗传风险有朝一日可能会被证明在临床上有用。我们使用病例对照数据集与MedSeq项目中独立发现的风险等位基因对多基因评分方法进行了比较。对于初级保健和心肌病研究队列中与临床相关的8个特征，我们使用161个已发表的风险等位基因估计乘性多基因风险分数，然后使用1000基因组计划估计的人群中位数进行归一化。我们的多基因评分方法在使用大规模全基因组关联研究数据集的情况下，与对照组相比，确定了独立发现的风险等位基因的过度表达。除了标准化的乘性多基因风险得分和在人群中的排名，已知常见风险变量解释的疾病患病率和遗传力比例为解释现代多位点疾病风险模型提供了重要背景。我们在MedSeq项目中的方法展示了如何总结和报告来自单个基因组的复杂特征风险变异，并向普通临床医生报告，并强调了最终临床研究的必要性，以获得此类估计的参考数据并建立临床实用价值。
Disease-causing mutations and pharmacogenomic variants are of primary interest for clinical whole-genome sequencing. However, estimating genetic liability for common complex diseases using established risk alleles might one day prove clinically useful. We compared polygenic scoring methods using a case-control data set with independently discovered risk alleles in the MedSeq Project. For eight traits of clinical relevance in both the primary-care and cardiomyopathy study cohorts, we estimated multiplicative polygenic risk scores using 161 published risk alleles and then normalized using the population median estimated from the 1000 Genomes Project. Our polygenic score approach identified the overrepresentation of independently discovered risk alleles in cases as compared with controls using a large-scale genome-wide association study data set. In addition to normalized multiplicative polygenic risk scores and rank in a population, the disease prevalence and proportion of heritability explained by known common risk variants provide important context in the interpretation of modern multilocus disease risk models. Our approach in the MedSeq Project demonstrates how complex trait risk variants from an individual genome can be summarized and reported for the general clinician and also highlights the need for definitive clinical studies to obtain reference data for such estimates and to establish clinical utility.