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首页> 外文期刊>BMC Neuroscience >Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia
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Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

机译：GWAS相关基因座上的新功能变异可能会给重度抑郁症，双相情感障碍和精神分裂症带来风险

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A challenge of understanding the mechanisms underlying cognition including neurodevelopmental and neuropsychiatric disorders is mainly given by the potential severity of cognitive disorders for the quality of life and their prevalence. However, the field has been focused predominantly on protein coding variation until recently. Given the importance of tightly controlled gene expression for normal brain function, the goal of the study was to assess the functional variation including non-coding variation in human genome that is likely to play an important role in cognitive functions. To this end, we organized and utilized available genome-wide datasets from genomic, transcriptomic and association studies into a comprehensive data corpus. We focused on genomic regions that are enriched in regulatory activity—overlapping transcriptional factor binding regions and repurpose our data collection especially for identification of the regulatory SNPs (rSNPs) that showed associations both with allele-specific binding and allele-specific expression. We matched these rSNPs to the nearby and distant targeted genes and then selected the variants that could implicate the etiology of cognitive disorders according to Genome-Wide Association Studies (GWAS). Next, we use DeSeq 2.0 package to test the differences in the expression of the certain targeted genes between the controls and the patients that were diagnosed bipolar affective disorder and schizophrenia. Finally, we assess the potential biological role for identified drivers of cognition using DAVID and GeneMANIA. As a result, we selected fourteen regulatory SNPs locating within the loci, implicated from GWAS for cognitive disorders with six of the variants unreported previously. Grouping of the targeted genes according to biological functions revealed the involvement of processes such as ‘posttranscriptional regulation of gene expression’, ‘neuron differentiation’, ‘neuron projection development’, ‘regulation of cell cycle process’ and ‘protein catabolic processes’. We identified four rSNP-targeted genes that showed differential expression between patient and control groups depending on brain region: NRAS—in schizophrenia cohort, CDC25B, DDX21 and NUCKS1—in bipolar disorder cohort. Overall, our findings are likely to provide the keys for unraveling the mechanisms that underlie cognitive functions including major depressive disorder, bipolar disorder and schizophrenia etiopathogenesis.
机译：理解包括神经发育和神经精神疾病在内的认知机制的挑战主要来自认知障碍对生活质量及其患病率的潜在严重性。然而，直到最近，该领域主要集中在蛋白质编码变异上。考虑到严格控制基因表达对于正常脑功能的重要性，该研究的目的是评估功能变异，包括可能在认知功能中起重要作用的人类基因组中的非编码变异。为此，我们将基因组，转录组学和关联研究的可用全基因组数据集组织和利用为一个综合的数据集。我们专注于富含调节活性的基因组区域-重叠转录因子结合区，并重新利用我们的数据收集，尤其是用于鉴定显示与等位基因特异性结合和等位基因特异性表达相关的调节性SNP（rSNPs）。我们将这些rSNP与附近和远处的靶基因进行了匹配，然后根据全基因组关联研究（GWAS）选择了可能暗示认知障碍病因的变体。接下来，我们使用DeSeq 2.0软件包来测试对照组和被诊断为双相情感障碍和精神分裂症的患者之间某些靶向基因的表达差异。最后，我们使用DAVID和GeneMANIA评估了识别出的认知驱动因素的潜在生物学作用。结果，我们选择了位于基因座内的十四个调节性SNP，它们与GWAS有关，涉及认知障碍，其中六个变体先前未报道。根据生物学功能对目标基因进行分组显示，这些过程涉及“基因表达的转录后调控”，“神经元分化”，“神经元投射发育”，“细胞周期过程调控”和“蛋白质分解代谢过程”。我们鉴定了四个针对rSNP的基因，这些基因在患者和对照组之间的差异取决于大脑区域：在精神分裂症队列中为NRAS，在双相情感障碍队列中为CDC25B，DDX21和NUCKS1。总体而言，我们的发现可能为阐明认知功能基础的机制提供关键，这些机制包括主要的抑郁症，躁郁症和精神分裂症的病因。

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