Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages.
Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages.
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DOI：
10.1371/journal.pgen.1002592
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Courchesne E
中科院分区：
文献类型：
--
作者：
Chow ML;Pramparo T;Winn ME;Barnes CC;Li HR;Weiss L;Fan JB;Murray S;April C;Belinson H;Fu XD;Wynshaw-Boris A;Schork NJ;Courchesne E
自闭症是一种高度遗传的神经发育障碍，然而这种疾病的遗传基础在很大程度上是未知的。异常的大脑过度生长在自闭症文献中得到了很好的重复观察；但是关联、联系和表达研究并没有发现解释这一轨迹的遗传因素。很少有研究具有足够的统计能力来研究自闭症大脑中的全基因组基因表达和基因型变异，特别是在表现出最大生长异常的区域。先前的功能基因组研究已经确定了与神经发育和免疫功能相关的基因转录水平的可能改变。因此，有必要进行涉及关键大脑区域的遗传研究，以复制这些发现，并巩固自闭症发病机制中特定功能通路的作用。因此，我们试图通过对自闭症患者和对照组死后脑样本的mRNA水平和拷贝数变异（CNVs）的全基因组分析来识别异常的脑基因表达模式。我们关注的是前额皮质组织，那里的神经元数量过多，皮层过度生长在大多数自闭症病例中都很明显。我们发现了在青少年自闭症前额叶皮层中控制细胞数量、皮质模式和分化的通路失调的证据。相比之下，成年自闭症患者的前额叶皮层则表现出信号和修复通路的失调。调节细胞周期的基因在来自前额皮质的DNA中也表现出自闭症特异性的CNVs，这些基因在全基因组关联研究数据集中与自闭症显著相关。我们的研究结果表明，自闭症中CNVs和年龄依赖性基因表达的变化可能反映了自闭症前额叶皮层发育与成熟的不同病理过程。我们的研究结果提出了一种假设，即发育中的大脑基因失调导致自闭症患者的区域模式异常、前额叶神经元过多、皮质过度生长和神经功能障碍。自闭症是一种以异常的社交、沟通、限制和重复行为为特征的疾病。它在生命的头几年临床发展。幼儿和自闭症儿童通常表现出早期大脑发育和前额皮质神经元数量过多。患有自闭症的成年人通常不会表现出大脑变大，反而可能有更小的大脑。因此，我们研究了年轻和成年死后自闭症患者前额叶皮层的DNA和mRNA模式，以确定年龄相关的基因表达差异，以及该疾病中异常脑增大、神经元数量过多和功能异常的可能遗传相关性。我们发现自闭症患者控制细胞数量、神经发育和皮层偏侧的遗传通路异常。我们还发现，与自闭症相关的关键途径在年轻和老年自闭症患者之间是不同的。这些发现表明，在神经发育的早期阶段失调的基因通路可能导致后来与自闭症相关的行为和认知缺陷。
Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism. Autism is a disorder characterized by aberrant social, communication, and restricted and repetitive behaviors. It develops clinically in the first years of life. Toddlers and children with autism often exhibit early brain enlargement and excess neuron numbers in the prefrontal cortex. Adults with autism generally do not display enlargement but instead may have a smaller brain size. Thus, we investigated DNA and mRNA patterns in prefrontal cortex from young versus adult postmortem individuals with autism to identify age-related gene expression differences as well as possible genetic correlates of abnormal brain enlargement, excess neuron numbers, and abnormal functioning in this disorder. We found abnormalities in genetic pathways governing cell number, neurodevelopment, and cortical lateralization in autism. We also found that the key pathways associated with autism are different between younger and older autistic individuals. These findings suggest that dysregulated gene pathways in the early stages of neurodevelopment could lead to later behavioral and cognitive deficits associated with autism.
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影响因子：
5.2
作者：
Carreira, Bruno Pereira;Morte, Maria Ines;Araujo, Ines Maria
通讯作者：
Araujo, Ines Maria
影响因子：
5.7
作者：
Carper, RA;Moses, P;Courchesne, E
通讯作者：
Courchesne, E
影响因子：
10.6
作者：
Carper, RA;Courchesne, E
通讯作者：
Courchesne, E
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
5.8
作者：
Falcon, S.;Gentleman, R.
通讯作者：
Gentleman, R.