Networks of neuronal genes affected by common and rare variants in autism spectrum disorders.
Networks of neuronal genes affected by common and rare variants in autism spectrum disorders.
复制标题
DOI：
10.1371/journal.pgen.1002556
复制
发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Shifman S
中科院分区：
文献类型：
--
作者：
Ben-David E;Shifman S
自闭症谱系障碍（ASD）是具有表型和遗传异质性的神经发育障碍。最近的研究报道了ASD中罕见的和新生的突变，但ASD的等位基因结构仍不清楚。为了评估常见和罕见变异在ASD中的作用，我们基于对人类大脑基因表达的广泛调查构建了一个基因共表达网络。我们确定了与特定细胞类型和过程相关的模块。通过整合已知的罕见突变和ASD全基因组关联研究（GWAS）的结果，我们确定了两个受到罕见和常见变异干扰的神经元模块。这些模块包含高度关联的基因，这些基因参与突触和神经元的可塑性，并在与学习、记忆和感觉知觉相关的区域表达。在另外两个包括单一和多重家族的样本中复制了常见风险变异的富集。一项对神经元模块中常见变异的综合贡献的分析揭示了多基因成分对ASD风险的影响。这项研究的结果指出，神经基因的两个亚网络的轻微和重大扰动对ASD风险的贡献。自闭症谱系障碍（ASD）是一种具有很强遗传基础的神经发育综合征，但受许多不同基因的影响。最近的研究已经确定了多种遗传风险因素，包括人群中常见的罕见突变和遗传变异。为了确定不同遗传风险因素之间可能的联系，我们构建了一个基于不同大脑区域基因表达模式的网络。我们确定了在整个大脑中以相似模式表达的几组基因，这表明它们参与了相同的过程或细胞类型。我们发现遗传危险因素在特定的连接基因群中富集。其中，在一组神经元基因中发现了最强的富集，这些基因与学习和记忆过程有关，并且在婴儿期高度表达。对这组基因的进一步研究有可能揭示导致ASD的更详细的神经元机制，并为开发诊断工具和有效治疗提供所需的知识。
Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk. Autism spectrum disorders (ASD) are neurodevelopmental syndromes with a strong genetic basis, but are influenced by many different genes. Recent studies have identified multiple genetic risk factors, including rare mutations and genetic variations common in the population. To identify possible connections between different genetic risk factors, we constructed a network based on the expression pattern of genes across different brain areas. We identified groups of genes that are expressed in a similar pattern across the brain, suggesting that they are involved in the same processes or types of cells. We found that the genetic risk factors were enriched in specific groups of connected genes. Of these, the strongest enrichment was discovered in a group of neuronal genes that are involved in processes of learning and memory, and are highly expressed during infancy. Further study of this group of genes has the potential to reveal a more detailed picture of the neuronal mechanisms leading to ASD and to provide knowledge required for developing diagnostic tools and effective therapies.
登录
查看更多内容
影响因子：
10.6
作者：
Carayol, Jerome;Sacco, Roberto;Persico, Antonio M.
通讯作者：
Persico, Antonio M.
影响因子：
5.2
作者：
Holt, Richard;Barnby, Gabrielle;Monaco, Anthony P.
通讯作者：
Monaco, Anthony P.
影响因子：
16.2
作者：
Ehninger, Dan;Li, Weidong;Fox, Kevin;Stryker, Michael P.;Silva, Alcino J.
通讯作者：
Silva, Alcino J.
影响因子：
3.3
作者：
Kim, S. Y.;Mo, J. W.;Kim, H.
通讯作者：
Kim, H.
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M