Department of Health Data Science Research, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Medical Center, Tokyo, Japan.
Laboratory of Evolutionary Genomics, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
BMC Med Genomics. 2020 Mar 29;13(1):55. doi: 10.1186/s12920-020-0699-9.
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.
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.
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.
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.
拷贝数变异（CNVs）已被报道与疾病、特征和进化有关。然而，如果 CNV 是罕见的或单一的，那么确定哪个基因应该优先作为进一步功能实验的目标是很困难的。在这项研究中，我们试图通过两种方法来克服这个问题：评估基因剂量敏感性和基因表达敏感性的影响。在之前的研究中，我们通过两轮全基因组复制得到了剂量敏感基因。此外，我们提出了一种跨学科的组学方法，利用 GTEx 的公开数据来评估全基因组 CNV 对基因表达的影响。
我们使用 Affymetrix Genome-Wide SNP Array 6.0 通过 PennCNV 和 CNV Workshop 来检测 CNVs。在进行了人群分层、家族关系和 CNV 检测的质量控制后，287 名发作性睡病患者、133 名特发性嗜睡症患者、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 名健康个体被保留用于富集分析。
总的来说，在发作性睡病、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。特别是，在所有疾病中，除了阿尔茨海默病之外，都观察到了与全基因组 CNV 相关的剂量敏感基因的显著富集。对于缺失，与健康个体相比，患者中缺失的剂量敏感基因较少或没有富集。有趣的是，在惊恐障碍和自闭症患者中观察到了与脑内基因表达敏感性相关的显著富集。虽然重复出现的负担更高，但与健康个体相比，缺失并没有造成显著差异。当我们同时评估基因组剂量和基因表达敏感性的影响时，在同时包含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了最高的富集比。此外，还研究了五种神经精神疾病之间的共享 CNV 区域。
这项研究提供了证据表明，在神经精神疾病中，剂量敏感基因与 CNV 有关。此外，我们利用 GTEx 的公开数据来评估全基因组 CNV 对基因表达的影响。我们还研究了神经精神疾病之间的共享 CNV 区域。
