Clinical assessment incorporating a personal genome.
Clinical assessment incorporating a personal genome.
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DOI：
10.1016/s0140-6736(10)60452-7
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发表时间：
2010-05-01
期刊：
影响因子：
168.9
通讯作者：
Altman, Russ B.
中科院分区：
文献类型：
--
作者：
Ashley, Euan A.;Butte, Atul J.;Wheeler, Matthew T.;Chen, Rong;Klein, Teri E.;Dewey, Frederick E.;Dudley, Joel T.;Ormond, Kelly E.;Pavlovic, Aleksandra;Morgan, Alexander A.;Pushkarev, Dmitry;Neff, Norma F.;Hudgins, Louanne;Gong, Li;Hodges, Laura M.;Berlin, Dorit S.;Thorn, Caroline F.;Sangkuhl, Katrin;Hebert, Joan M.;Woon, Mark;Sagreiya, Hersh;Whaley, Ryan;Knowles, Joshua W.;Chou, Michael F.;Thakuria, Joseph V.;Rosenbaum, Abraham M.;Zaranek, Alexander Wait;Church, George M.;Greely, Henry T.;Quake, Stephen R.;Altman, Russ B.
基因组信息的成本急剧下降，但在全基因组关联研究中发现的常见变异的风险估计的临床转化途径仍不清楚。由于全基因组测序的速度和成本正在迅速下降，因此需要更全面的方法来分析这些数据，并结合罕见变异进行遗传风险评估和个性化治疗。在这里，我们提出了一个完整的人类基因组在临床背景下的第一个综合分析。一个有血管疾病和早期猝死家族史的个体被评估。临床评估包括冠状动脉疾病风险预测、心源性猝死原因筛查和遗传咨询。遗传分析包括开发整合全基因组序列数据的新方法，包括260万个单核苷酸多态性和752个拷贝数变异。该算法专注于预测与已知孟德尔病相关基因的遗传风险、已识别的药物反应以及新变异的致病性。此外，由于整合来自病例对照研究的风险比具有挑战性，我们估计了年龄和性别合适的先验概率和每种基因型的似然比的后验概率。此外，我们开发了一种可视化方法来解释基因-环境相互作用和条件依赖性风险。我们发现心肌梗塞、二型糖尿病和某些癌症的遗传风险增加了。LPA的罕见变异与冠状动脉疾病的家族史一致。药物基因组学分析表明对降脂治疗有积极反应，可能对氯吡格雷耐药，华法林初始剂量低。许多不确定意义的变异被报道。尽管挑战仍然存在，但我们的研究结果表明，全基因组测序可以为个体患者提供有用的和临床相关的信息，特别是对于那些有严重疾病家族史的患者。
The cost of genomic information has fallen steeply but the path to clinical translation of risk estimates for common variants found in genome wide association studies remains unclear. Since the speed and cost of sequencing complete genomes is rapidly declining, more comprehensive means of analyzing these data in concert with rare variants for genetic risk assessment and individualisation of therapy are required. Here, we present the first integrated analysis of a complete human genome in a clinical context. An individual with a family history of vascular disease and early sudden death was evaluated. Clinical assessment included risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome sequence data including 2.6 million single nucleotide polymorphisms and 752 copy number variations. The algorithm focused on predicting genetic risk of genes associated with known Mendelian disease, recognised drug responses, and pathogenicity for novel variants. In addition, since integration of risk ratios derived from case control studies is challenging, we estimated posterior probabilities from age and sex appropriate prior probability and likelihood ratios derived for each genotype. In addition, we developed a visualisation approach to account for gene-environment interactions and conditionally dependent risks. We found increased genetic risk for myocardial infarction, type II diabetes and certain cancers. Rare variants in LPA are consistent with the family history of coronary artery disease. Pharmacogenomic analysis suggested a positive response to lipid lowering therapy, likely clopidogrel resistance, and a low initial dosing requirement for warfarin. Many variants of uncertain significance were reported. Although challenges remain, our results suggest that whole genome sequencing can yield useful and clinically relevant information for individual patients, especially for those with a strong family history of significant disease.