Prioritizing Autism Risk Genes using Personalized Graphical Models Estimated from Single Cell RNA-seq Data.
Prioritizing Autism Risk Genes using Personalized Graphical Models Estimated from Single Cell RNA-seq Data.
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DOI：
10.1080/01621459.2021.1933495
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发表时间：
2022
影响因子：
3.7
通讯作者：
Liu, Yufeng
中科院分区：
文献类型：
--
作者：
Liu, Jianyu;Wang, Haodong;Sun, Wei;Liu, Yufeng
最近报道了数百个自闭症风险基因，主要基于遗传学研究，这些风险基因在自闭症受试者中比健康对照组有更多的新生突变。然而，作为一种复杂的疾病，自闭症可能与更多的风险基因有关，其中许多可能无法通过从头突变来识别。我们假设更多的自闭症风险基因可以通过它们与个性化基因-基因相互作用图中已知的自闭症风险基因的联系来识别。我们使用单细胞 RNA 测序 (scRNA-seq) 来估计此类个性化图表，同时对 scRNA-seq 数据中的细胞依赖性和可能的零膨胀进行适当建模。在我们使用自闭症受试者和对照的 scRNA-seq 数据进行的案例研究中，样本量（即每个人的细胞数量）范围为 891 到 1,241。我们在分析中考虑了 1,500 个基因。由于基因数量较大或与样本量相当，因此我们进行惩罚估计。我们通过对每个个性化图应用简单的图核平滑方法来对每个基因的相关性进行评分。得分最高的基因的分子功能与自闭症疾病有关。例如，编码兰尼碱受体 2 蛋白的候选基因 RYR2 参与神经传递，而自闭症谱系障碍患者的这一过程会受到损害。虽然我们的方法提供了一种系统且公正的方法来优先考虑自闭症风险基因，但这些基因的相关性需要在功能研究中进一步验证。
Hundreds of autism risk genes have been reported recently, mainly based on genetic studies where these risk genes have more de novo mutations in autism subjects than healthy controls. However, as a complex disease, autism is likely associated with more risk genes and many of them may not be identifiable through de novo mutations. We hypothesize that more autism risk genes can be identified through their connections with known autism risk genes in personalized gene-gene interaction graphs. We estimate such personalized graphs using single cell RNA sequencing (scRNA-seq) while appropriately modeling the cell dependence and possible zero-inflation in the scRNA-seq data. The sample size, which is the number of cells per individual, ranges from 891 to 1,241 in our case study using scRNA-seq data in autism subjects and controls. We consider 1,500 genes in our analysis. Since the number of genes is larger or comparable to the sample size, we perform penalized estimation. We score each gene’s relevance by applying a simple graph kernel smoothing method to each personalized graph. The molecular functions of the top-scored genes are related to autism diseases. For example, a candidate gene RYR2 that encodes protein ryanodine receptor 2 is involved in neurotransmission, a process that is impaired in ASD patients. While our method provides a systemic and unbiased approach to prioritize autism risk genes, the relevance of these genes needs to be further validated in functional studies.
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影响因子：
48
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
14.8
作者：
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通讯作者：
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