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Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases.
BMC Medical Genomics ( IF 2.7 ) Pub Date : 2020-03-29 , DOI: 10.1186/s12920-020-0699-9
Maria Yamasaki 1 , Takashi Makino 2 , Seik-Soon Khor 3 , Hiromi Toyoda 3, 4 , Taku Miyagawa 5 , Xiaoxi Liu 6 , Hitoshi Kuwabara 7 , Yukiko Kano 8, 9 , Takafumi Shimada 10 , Toshiro Sugiyama 8 , Hisami Nishida 11 , Nagisa Sugaya 12 , Mamoru Tochigi 13 , Takeshi Otowa 14 , Yuji Okazaki 15 , Hisanobu Kaiya 16 , Yoshiya Kawamura 17 , Akinori Miyashita 18 , Ryozo Kuwano 18, 19 , Kiyoto Kasai 20 , Hisashi Tanii 21 , Tsukasa Sasaki 22 , Makoto Honda 5 , Katsushi Tokunaga 3, 4
Affiliation  

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.

中文翻译:

对基因剂量和基因表达的敏感性影响在神经精神疾病中观察到具有拷贝数变异的基因。

拷贝数变异(CNV)已被报道与疾病,特征和进化有关。但是,如果CNV罕见或单例,则很难确定哪个基因应优先作为进一步功能实验的靶标。在这项研究中,我们试图通过两种方法克服这一问题:评估基因剂量敏感性和基因表达敏感性的影响。剂量敏感基因来自先前研究中的两轮全基因组复制。此外,我们提出了一种横截面组学方法,该方法利用来自GTEx的开放数据来评估全基因组CNV对基因表达的影响。PennCNV和CNV Workshop使用Affymetrix全基因组SNP Array 6.0检测CNV。在对人群分层,家庭关系和CNV检测进行质量控制后,仍有287例发作性睡病,133例原发性失眠,380例惊恐障碍,164例自闭症,784例阿尔茨海默氏病和1280名健康个体进行了富集分析。总体而言,在发作性睡病,恐慌症和自闭症患者中发现了剂量敏感基因的大量富集。特别是,在除阿尔茨海默氏病之外的所有疾病中,都发现重复存在剂量敏感性基因的大量富集。对于缺失,与健康个体相比,在患者中观察到较少或没有富集剂量敏感性基因的缺失。有趣的是,在恐慌症和自闭症患者中观察到脑中具有表达敏感性的基因大量富集。尽管重复会带来更高的负担,与健康个体相比,缺失没有引起显着差异。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,在包括剂量敏感性基因和仅在大脑中具有表达敏感性的基因的组中观察到最高的富集率。此外,还调查了五种神经精神疾病中共享的CNV区域。这项研究提供了证据,证明剂量敏感性基因与神经精神疾病中的CNV相关。此外,我们利用来自GTEx的公开数据来评估全基因组CNV对基因表达的影响。我们还调查了神经精神疾病之间共享的CNV区域。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,在包括剂量敏感性基因和仅在大脑中具有表达敏感性的基因的组中观察到最高的富集率。此外,还调查了五种神经精神疾病中共享的CNV区域。这项研究提供了证据,证明剂量敏感性基因与神经精神疾病中的CNV相关。此外,我们利用来自GTEx的公开数据来评估全基因组CNV对基因表达的影响。我们还调查了神经精神疾病之间共享的CNV区域。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,在包括剂量敏感性基因和仅在大脑中具有表达敏感性的基因的组中观察到最高的富集率。此外,还调查了五种神经精神疾病中共享的CNV区域。这项研究提供了证据,证明剂量敏感性基因与神经精神疾病中的CNV相关。此外,我们利用来自GTEx的公开数据来评估全基因组CNV对基因表达的影响。我们还调查了神经精神疾病之间共享的CNV区域。还调查了五种神经精神疾病中共享的CNV区域。这项研究提供了证据,证明剂量敏感性基因与神经精神疾病之间的CNV相关。此外,我们利用来自GTEx的公开数据来评估全基因组CNV对基因表达的影响。我们还调查了神经精神疾病之间共享的CNV区域。还调查了五种神经精神疾病中共享的CNV区域。这项研究提供了证据,证明剂量敏感性基因与神经精神疾病中的CNV相关。此外,我们利用来自GTEx的公开数据来评估全基因组CNV对基因表达的影响。我们还调查了神经精神疾病之间共享的CNV区域。
更新日期:2020-04-22
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