A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci.
A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci.
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DOI：
10.1371/journal.pgen.1001292
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发表时间：
2011-02-03
期刊：
影响因子：
4.5
通讯作者：
Cox NJ
中科院分区：
文献类型：
--
作者：
Gamazon ER;Nicolae DL;Cox NJ
我们对snp （r2≥0.8）标记良好的拷贝数变异（CNVs）进行了全面研究，分析了它们对基因表达的影响及其与疾病易感性和其他复杂人类性状的关联。我们测试了这些CNVs是否比频率匹配的snp更有可能作为性状相关位点或作为表达数量性状位点（eQTLs）通过改变基因调控影响表型。我们的研究发现，cnv标记snp在cis eqtl中显著富集；此外，我们观察到来自NHGRI目录的性状关联显示，相对于频率匹配的snp，标记CNVs的snp过多。我们发现这些标记CNVs的snp比频率匹配的变体更有可能影响多种表达特征。鉴于这些关于CNVs功能相关性的发现，我们利用最全面的CNVs群体图谱创建了一个表达相关CNVs （eCNVs）的在线资源，为未来复杂性状的研究提供信息。尽管先前对可在现有平台上分型和/或在全基因组关联研究中被snp询问的常见CNVs的研究得出结论，这些CNVs似乎不太可能在几种所检查的复杂疾病的遗传基础中起主要作用，但我们的研究结果表明，排除即使是常见CNVs也可能导致复杂表型和至少一些常见疾病的可能性还为时过早。尽管发现了大量与复杂疾病可重复相关的snp，但它们在这些性状的总体遗传力中只占很小的比例。因此，CNVs被提出用来解释一些缺失的遗传性和改变疾病易感性。然而，最近一项涉及16000例病例和3000例对照的8种常见疾病的遗传学研究未能发现任何与疾病相关的新型CNVs，并得出CNVs不太可能在其病因中发挥主要作用的结论。我们在此报告的研究表明，我们必须谨慎，不要忽视CNVs可能确实是一些观察到的复杂疾病关联的基础。我们的研究结果表明，与频率匹配的snp相比，标记良好的cnv不成比例地更有可能是eqtl和顺式eqtl；此外，如NHGRI目录中所示，与频率匹配的snp相比，标记良好的cnv具有丰富的可重复性状关联。由于这些发现与这些CNVs具有很强的功能相关性，我们创建了一个表达相关CNVs的数据库（可在http://www.scandb.org/上获得），以补充我们早期的SNP eqtl研究，并为未来复杂性状的遗传学研究做出贡献。
We conducted a comprehensive study of copy number variants (CNVs) well-tagged by SNPs (r2≥0.8) by analyzing their effect on gene expression and their association with disease susceptibility and other complex human traits. We tested whether these CNVs were more likely to be functional than frequency-matched SNPs as trait-associated loci or as expression quantitative trait loci (eQTLs) influencing phenotype by altering gene regulation. Our study found that CNV–tagging SNPs are significantly enriched for cis eQTLs; furthermore, we observed that trait associations from the NHGRI catalog show an overrepresentation of SNPs tagging CNVs relative to frequency-matched SNPs. We found that these SNPs tagging CNVs are more likely to affect multiple expression traits than frequency-matched variants. Given these findings on the functional relevance of CNVs, we created an online resource of expression-associated CNVs (eCNVs) using the most comprehensive population-based map of CNVs to inform future studies of complex traits. Although previous studies of common CNVs that can be typed on existing platforms and/or interrogated by SNPs in genome-wide association studies concluded that such CNVs appear unlikely to have a major role in the genetic basis of several complex diseases examined, our findings indicate that it would be premature to dismiss the possibility that even common CNVs may contribute to complex phenotypes and at least some common diseases. Despite the large number of SNPs found to be reproducibly associated with complex diseases, they collectively account for only a small proportion of the overall heritability to such traits. CNVs have thus been proposed to explain some of the missing heritability and to alter disease susceptibility. However, a recent study of the genetics of 8 common diseases involving 16,000 cases and 3,000 controls failed to identify any novel CNVs associated with disease and concluded that CNVs are unlikely to play a major role in their etiology. Studies we report here show that we must be careful not to dismiss the possibility that CNVs may indeed underlie some of the observed associations with complex disease. Our findings show that well-tagged CNVs are disproportionately more likely to be eQTLs, as well as cis-eQTLs, than frequency-matched SNPs; furthermore, reproducible trait associations, as represented in the NHGRI catalog, are enriched for well-tagged CNVs than frequency-matched SNPs. Because of these findings on the strong functional relevance of these CNVs, we created a database (available at http://www.scandb.org/) of expression associated CNVs to supplement our earlier studies of SNP eQTLs and to contribute to future studies of the genetics of complex traits.
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影响因子：
5.3
作者：
Zhang W;Duan S;Bleibel WK;Wisel SA;Huang RS;Wu X;He L;Clark TA;Chen TX;Schweitzer AC;Blume JE;Dolan ME;Cox NJ
通讯作者：
Cox NJ
影响因子：
5.8
作者：
Gamazon, Eric R.;Zhang, Wei;Cox, Nancy J.
通讯作者：
Cox, Nancy J.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.
影响因子：
3.5
作者：
McCarroll, Steven A.
通讯作者：
McCarroll, Steven A.