Prenatal expression patterns of genes associated with neuropsychiatric disorders.
Prenatal expression patterns of genes associated with neuropsychiatric disorders.
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DOI：
10.1176/appi.ajp.2014.13111452
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Weinberger DR
中科院分区：
文献类型：
--
作者：
Birnbaum R;Jaffe AE;Hyde TM;Kleinman JE;Weinberger DR
神经发育障碍可能涉及大脑发育过程中发生的事件。我们假设，在病因学上被认为是发育性的神经精神障碍与易感基因有关，这些易感基因在胎儿时期相对上调(即差异表达)。我们系统地研究了在基于微阵列的“BrainCloud”前额叶背外侧皮质(DLPFC)转录组中，作为与6种神经精神疾病相关的复合基因集，产前易感基因表达丰富的存在。以胎儿/出生后log2倍数变化阈值为0.5时，与总转录组相比，与综合征神经发育障碍(n=31个基因，p=3.37×10−3)、智能障碍(n=88个基因，p=5.53×10−3)和自闭症谱系障碍(n=242个基因，p=3.45×10−4)相关基因的产前转录丰度相对丰富。与精神分裂症相关的基因在胎儿期没有优先表达(n=106个基因，p=0.46)，外显子组测序也没有发现与精神分裂症相关的基因(n=212个基因，p=.21)，但与精神分裂症相关的CNV区域的特定基因在出生前转录丰度相对较高，Meta分析表明与精神分裂症相关的基因在某些神经发育过程中功能丰富。相反，与神经退行性疾病相关的基因在胎儿时期表达显著降低(n=46个基因，p=1.67×10−3)。我们发现，有证据表明，先证性神经发育障碍、智力残疾和自闭症谱系障碍的易感基因在出生前相对丰富。未来的转录组水平的关联研究应该在其他时间点评估DLPFC以外的区域，并纳入进一步的RNA测序分析。
Neurodevelopmental disorders presumably involve events that occur during brain development. We hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e. differentially expressed). We investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with 6 neuropsychiatric disorders in the microarray-based “BrainCloud” dorsolateral prefrontal cortex (DLPFC) transcriptome. Using a fetal/post-natal log2 fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (n = 31 genes, p = 3.37×10−3), intellectual disability (n = 88 genes, p = 5.53×10−3), and autism spectrum disorder (n = 242 genes, p = 3.45×10−4) were relatively enriched in prenatal transcript abundance, compared to the overall transcriptome. Genes associated with schizophrenia by GWAS were not preferentially fetal expressed (n = 106 genes, p = 0.46), nor were genes associated with schizophrenia by exome sequencing (n = 212 genes, p = .21), but specific genes within CNV regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (n = 46 genes, p = 1.67×10−3). We found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorders. Future transcriptome-level association studies should evaluate regions other than the DLPFC, at other time points, and incorporate further RNA sequencing analyses.
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