Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases
Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases
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DOI：
10.1186/s12920-020-0699-9
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发表时间：
2020-03-29
影响因子：
2.7
通讯作者：
Tokunaga, Katsushi
中科院分区：
文献类型：
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作者：
Yamasaki, Maria;Makino, Takashi;Tokunaga, Katsushi
研究背景拷贝数变异（Copy number variants，CNVs）与疾病、性状和进化有关。然而，如果CNV是罕见的或单例的，则很难确定哪个基因应该优先作为进一步功能实验的靶点。在本研究中，我们试图通过两种方法来克服这个问题：通过评估基因剂量敏感性和基因表达敏感性的影响。以往研究中剂量敏感基因来源于两轮全基因组复制。此外，我们提出了一种横断面组学方法，该方法利用GTEx的开放数据来评估全基因组CNV对基因表达的影响。方法应用Affyphine-Wide SNP Array 6.0检测CNVs。在对人群分层、家庭关系和CNV检测进行质量控制后，287名发作性睡病患者、133名原发性睡眠过度患者、380名惊恐障碍患者、164名自闭症患者、784名阿尔茨海默病患者和1280名健康个体仍用于富集分析。结果总体而言，在嗜睡症、惊恐障碍和自闭症患者中发现了剂量敏感基因的显著富集。特别地，在除阿尔茨海默病之外的所有疾病中观察到剂量敏感性基因在重复中的显著富集。对于缺失，与健康个体相比，在患者中观察到较少或没有缺失的剂量敏感基因富集。有趣的是，在惊恐障碍和自闭症患者中观察到大脑中具有表达敏感性的基因的显著富集。虽然重复呈现出更高的负担，但与健康个体相比，缺失并没有造成显著差异。当我们同时评估对基因组剂量和基因表达的敏感性的影响时，在包括剂量敏感基因和仅在脑中具有表达敏感性的基因的组中观察到最高的富集比率。此外，还调查了五种神经精神疾病之间的共享CNV区域。结论本研究为剂量敏感基因与神经精神疾病CNVs的发生相关提供了证据。此外，我们利用来自GTEx的开放数据来评估全基因组CNV对基因表达的影响。我们还调查了神经精神疾病之间的共享CNV区域。
Background Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. Methods Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. Results Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. Conclusions This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.