Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways
Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways
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DOI：
10.1093/hmg/dds164
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发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Pericak-Vance, Margaret A.
中科院分区：
文献类型：
--
作者：
Griswold, Anthony J.;Ma, Deqiong;Pericak-Vance, Margaret A.
自闭症谱系障碍（ASD）是高度遗传的，但相对较少的相关遗传位点已被复制。拷贝数变异（CNV）与自闭症有关;然而，大多数基因座与1个疾病人群有关。因此，独立的研究是重要的，以完善相关的CNV区域和发现新的易感基因。在这项研究中，全基因组SNP阵列被用于CNV检测两种不同的算法在欧洲血统的病例对照数据集。我们发现在ASD病例中，缺失的数量和大小明显更高，并且破坏了更多的基因。此外，18个大于1 Mb的缺失仅在病例中检测到，涉及2q22.1，3p26.3，4 q12和14 q23的新区域。病例特异性CNV为先前参与ASD的途径提供了进一步的证据，揭示了GABA能信号传导和神经发育途径中的新候选基因。这些包括DBI，GABA受体的变构结合剂，GABARAPL 1，GABA受体相关蛋白，和SLC 6A 11，突触后GABA转运蛋白。我们还确定了COBL中的CNVs，其缺失导致模型脊椎动物神经元细胞骨架形态发生的缺陷，以及DNER，小脑发育所需的神经元特异性Notch配体。此外，我们发现了自闭症与其他神经发育和神经精神疾病之间遗传重叠的证据。这些基因包括谷氨酸受体（GRID 1、GRIK 2和GRIK 4）、突触调节因子（NRXN 3、SLC 6A 8和SYN 3）、转录因子（ZNF 804 A）和RNA结合蛋白FMR 1。总的来说，这些CNV可能是ASD遗传性缺失的几个片段，并导致发现新的病因学机制。
Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to 1 of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry casecontrol data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.