Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia
Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia
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DOI：
10.1016/j.neuron.2019.05.013
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发表时间：
2019-07-17
期刊：
影响因子：
16.2
通讯作者：
Narurkar, Rujuta
中科院分区：
文献类型：
--
作者：
Collado-Torres, Leonardo;Burke, Emily E.;Narurkar, Rujuta
海马体的形成，虽然显着牵连在精神分裂症的发病机制，一直被忽视的大规模基因组学的努力，在精神分裂症的大脑。我们在551名个体（286名精神分裂症患者）的前额叶和背外侧前额叶皮质（DLPFC）中进行了RNA-seq。我们确定了基因表达的实质性区域差异，并发现了独立于细胞组成的广泛的发育差异。我们确定了48和245个差异表达基因（DEG）与海马和DLPFC内的精神分裂症，与大脑区域之间的重叠很少。在163个精神分裂症GWAS危险位点中，有124个（76.6%）在任何区域都存在eQTL。在每个区域进行的全转录组关联研究发现了许多新的精神分裂症风险特征，这些特征是大脑区域特异性的。最后，我们确定了精神分裂症患者额叶-海马功能一致性改变的体内证据的潜在分子相关性。这些结果强调了精神分裂症转录相关基因的复杂性和区域异质性，并为潜在的致病生物学提供了新的见解。
The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology.