整合功能评分和调控数据,预测非编码 SNPs 对一种复杂神经疾病的影响。

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Daniela Felício, Miguel Alves-Ferreira, Mariana Santos, Marlene Quintas, Alexandra M Lopes, Carolina Lemos, Nádia Pinto, Sandra Martins
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引用次数: 0

摘要

与复杂疾病相关的大多数 SNP 似乎都位于基因组的非编码区;然而,人们对这些 SNP 对基因表达和疾病表型的贡献仍然知之甚少。在此,我们建立了一个工作流程,以帮助确定候选基因的非编码 SNPs 作为多基因神经系统疾病易感位点的功能相关性。为了说明工作流程的适用性,我们将多因素疾病偏头痛作为一个模型,按照我们的方法逐步进行研究。我们注释了所选 SNP 与调控元件的重叠,并根据公开可用的预测算法和功能基因组学信息评估了它们对基因表达的潜在影响。一些偏头痛风险基因位点被假定位于非编码区,并与神经传递途径有关。在本研究中,我们使用了22个非编码SNPs,这些SNPs来自神经传递和突触机械相关基因,之前根据候选基因关联研究,这些基因被认为与偏头痛易感性有关。在对这些 SNP 进行优先排序后,我们重点研究了那些未报告的、具有高调控潜力的 SNP:(1)VAMP2_rs1150(3' UTR)被预测为 hsa-mir-5010-3p miRNA 的靶点,可能会干扰其自身基因的表达;(2)STX1A_rs6951030(近端增强子)可能会影响锌指转录因子(即 ZNF423)的结合亲和力,干扰 TBL2 基因的表达;(3)SNAP25_rs2327264(远端增强子)预计位于 ONECUT2 转录因子的结合位点。这项研究证明了我们的实用工作流程的适用性,它有助于对潜在相关的非编码 SNP 进行优先排序,并预测它们在多因素神经系统疾病中的功能影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrating functional scoring and regulatory data to predict the effect of non-coding SNPs in a complex neurological disease.

Most SNPs associated with complex diseases seem to lie in non-coding regions of the genome; however, their contribution to gene expression and disease phenotype remains poorly understood. Here, we established a workflow to provide assistance in prioritising the functional relevance of non-coding SNPs of candidate genes as susceptibility loci in polygenic neurological disorders. To illustrate the applicability of our workflow, we considered the multifactorial disorder migraine as a model to follow our step-by-step approach. We annotated the overlap of selected SNPs with regulatory elements and assessed their potential impact on gene expression based on publicly available prediction algorithms and functional genomics information. Some migraine risk loci have been hypothesised to reside in non-coding regions and to be implicated in the neurotransmission pathway. In this study, we used a set of 22 non-coding SNPs from neurotransmission and synaptic machinery-related genes previously suggested to be involved in migraine susceptibility based on our candidate gene association studies. After prioritising these SNPs, we focused on non-reported ones that demonstrated high regulatory potential: (1) VAMP2_rs1150 (3' UTR) was predicted as a target of hsa-mir-5010-3p miRNA, possibly disrupting its own gene expression; (2) STX1A_rs6951030 (proximal enhancer) may affect the binding affinity of zinc-finger transcription factors (namely ZNF423) and disturb TBL2 gene expression; and (3) SNAP25_rs2327264 (distal enhancer) expected to be in a binding site of ONECUT2 transcription factor. This study demonstrated the applicability of our practical workflow to facilitate the prioritisation of potentially relevant non-coding SNPs and predict their functional impact in multifactorial neurological diseases.

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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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