Rare variants in ischemic stroke: an exome pilot study.
Rare variants in ischemic stroke: an exome pilot study.
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DOI：
10.1371/journal.pone.0035591
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
O'Connell JR
中科院分区：
文献类型：
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作者：
Cole JW;Stine OC;Liu X;Pratap A;Cheng Y;Tallon LJ;Sadzewicz LK;Dueker N;Wozniak MA;Stern BJ;Meschia JF;Mitchell BD;Kittner SJ;O'Connell JR
缺血性卒中的遗传结构是复杂的，可能包括罕见或低频率的变异，具有高突变率和大效应量。与具有小效应量的常见变异相比，此类变异可能提供对疾病发病机制的重要见解。由于人类功能变异的很大一部分可能来自基因的蛋白质编码部分，我们进行了一项初步研究以鉴定整个人类外显子组的变异（即，整个人类基因组的编码外显子）。我们的努力集中在评估可行性和确定这类研究的困难，因为它适用于缺血性中风。这些病例包括8名非洲裔美国人和2名白人，他们是根据相似的中风亚型和实施强调中风风险遗传贡献的病例选择算法选择的。在构建双端测序文库后，捕获每个样品中的所有预测的人外显子并测序。测序平均产生2550万个读取对（75 bp×2）和每个样品3.8 Gbp。在通过质量过滤器后，针对dbSNP筛选外显子组，在非裔美国人中平均发现2839个新的SNP，在高加索人中平均发现1105个。在一项综合分析中，在所有中风病例中，48个基因被鉴定出至少有一种罕见变异。一个基因，CSN3，通过筛选我们以前的GWAS结果结合我们的外显子组结果，被发现含有一个有趣的编码多态性，以及含有过量的罕见变异相比，其他基因的评价。总之，虽然罕见的编码变异可能易患缺血性卒中的风险，这一事实尚未得到明确的证明。我们的研究表明了这种研究的复杂性，并强调虽然可以获得外显子组数据，但最佳分析方法尚未确定。
The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined.
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影响因子：
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作者：
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通讯作者：
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使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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