Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
PLoS Genet. 2011 Feb 3;7(2):e1001292. doi: 10.1371/journal.pgen.1001292.
We conducted a comprehensive study of copy number variants (CNVs) well-tagged by SNPs (r(2)≥ 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.
我们通过分析其对基因表达的影响及其与疾病易感性和其他复杂人类特征的关联，对 SNP 标记良好的拷贝数变异（CNVs）进行了全面研究（r(2)≥0.8）。我们测试了这些 CNVs 是否比频率匹配的 SNP 更有可能作为与性状相关的基因座或作为影响表型的表达数量性状基因座（eQTLs），通过改变基因调控而成为功能变体。我们的研究发现，CNV 标记 SNP 明显富集 cis-eQTL；此外，我们观察到 NHGRI 目录中的性状关联显示出相对于频率匹配 SNP 的 CNV 标记 SNP 的过度表示。我们发现，这些标记 CNV 的 SNP 比频率匹配的变体更有可能影响多个表达性状。鉴于对 CNV 功能相关性的这些发现，我们使用最全面的基于人群的 CNV 图谱创建了一个与表达相关的 CNV（eCNV）在线资源，以告知未来对复杂性状的研究。尽管先前对常见 CNV 的研究可以在现有平台上进行分型和/或通过全基因组关联研究中的 SNP 进行检测，但这些研究得出的结论是，此类 CNV 似乎不太可能在已检查的几种复杂疾病的遗传基础中起主要作用，我们的研究结果表明，即使常见的 CNV 可能有助于复杂的表型，至少是一些常见疾病，也可能过早地否定这种可能性。
