PDF(Pubmed)
Abstract：
UNASSIGNED: The prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. Here, we combined high-resolution single-nuclei RNA sequencing data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder.
UNASSIGNED: Gene expression specificity values were calculated from a single-nuclei RNA sequencing dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood. Enrichment of schizophrenia common variant liability and burden of rare protein-truncating coding variants were tested in genes with high expression specificity for each cell type. We also explored schizophrenia common variant associations in relation to gene expression across the developmental trajectory of implicated neurons.
UNASSIGNED: Common risk variation for schizophrenia was prominently enriched in genes with high expression specificity for a population of mature layer 4 glutamatergic neurons emerging in infancy. Common variant liability to schizophrenia increased along the developmental trajectory of this neuronal population. Fine-mapped genes at schizophrenia genome-wide association study risk loci had significantly higher expression specificity than other genes in these neurons and in a population of layer 5/6 glutamatergic neurons. People with schizophrenia had a higher rate of rare protein-truncating coding variants in genes expressed by cells of the PFC than control individuals, but no cell population was significantly enriched above this background rate.
UNASSIGNED: We identified a population of layer 4 glutamatergic PFC neurons likely to be particularly affected by common variant genetic risk for schizophrenia, which may contribute to disturbances in thalamocortical connectivity in the condition.
The prefrontal cortex (PFC) has been strongly implicated in the underlying biology of schizophrenia. We tested whether specific cell populations within the PFC preferentially express genes that increase risk for the disorder. We found that a particular type of PFC neuron prominently expresses genes associated with schizophrenia, suggesting its involvement in the condition.
UNASSIGNED: Gene expression specificity values were calculated from a single-nuclei RNA sequencing dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood. Enrichment of schizophrenia common variant liability and burden of rare protein-truncating coding variants were tested in genes with high expression specificity for each cell type. We also explored schizophrenia common variant associations in relation to gene expression across the developmental trajectory of implicated neurons.
UNASSIGNED: Common risk variation for schizophrenia was prominently enriched in genes with high expression specificity for a population of mature layer 4 glutamatergic neurons emerging in infancy. Common variant liability to schizophrenia increased along the developmental trajectory of this neuronal population. Fine-mapped genes at schizophrenia genome-wide association study risk loci had significantly higher expression specificity than other genes in these neurons and in a population of layer 5/6 glutamatergic neurons. People with schizophrenia had a higher rate of rare protein-truncating coding variants in genes expressed by cells of the PFC than control individuals, but no cell population was significantly enriched above this background rate.
UNASSIGNED: We identified a population of layer 4 glutamatergic PFC neurons likely to be particularly affected by common variant genetic risk for schizophrenia, which may contribute to disturbances in thalamocortical connectivity in the condition.
The prefrontal cortex (PFC) has been strongly implicated in the underlying biology of schizophrenia. We tested whether specific cell populations within the PFC preferentially express genes that increase risk for the disorder. We found that a particular type of PFC neuron prominently expresses genes associated with schizophrenia, suggesting its involvement in the condition.
摘要：
■前额叶皮层（PFC）与精神分裂症的病理生理学密切相关。这里,我们将来自人类PFC的高分辨率单核RNA测序数据与精神分裂症的大规模基因组数据相结合,以确定可能介导该疾病遗传倾向的组成细胞群体.
■基因表达特异性值是从包含来自人类PFC的84个细胞群体的单核RNA测序数据集计算的。从怀孕到成年.在对每种细胞类型具有高表达特异性的基因中测试了精神分裂症常见变体责任的富集和稀有蛋白质截断编码变体的负担。我们还探索了精神分裂症常见的变异关联与涉及神经元发育轨迹中基因表达的关系。
■精神分裂症的常见风险变异在婴儿期出现的成熟4层谷氨酸能神经元群体中具有高表达特异性的基因中显著富集。精神分裂症的常见变异责任沿着该神经元群体的发展轨迹增加。精神分裂症全基因组关联研究风险位点的精细定位基因在这些神经元和5/6层谷氨酸能神经元群体中的表达特异性明显高于其他基因。精神分裂症患者在PFC细胞表达的基因中罕见蛋白截短编码变异的发生率高于对照组。但是没有细胞群体显著富集超过这个背景率。
■我们确定了一组4层谷氨酸能PFC神经元可能特别受到精神分裂症常见变异遗传风险的影响，这可能会导致该病的丘脑皮质连通性紊乱。
前额叶皮层（PFC）与精神分裂症的潜在生物学密切相关。我们测试了PFC内的特定细胞群体是否优先表达增加疾病风险的基因。我们发现特定类型的PFC神经元显著表达与精神分裂症相关的基因，表明它参与了这种情况。
■基因表达特异性值是从包含来自人类PFC的84个细胞群体的单核RNA测序数据集计算的。从怀孕到成年.在对每种细胞类型具有高表达特异性的基因中测试了精神分裂症常见变体责任的富集和稀有蛋白质截断编码变体的负担。我们还探索了精神分裂症常见的变异关联与涉及神经元发育轨迹中基因表达的关系。
■精神分裂症的常见风险变异在婴儿期出现的成熟4层谷氨酸能神经元群体中具有高表达特异性的基因中显著富集。精神分裂症的常见变异责任沿着该神经元群体的发展轨迹增加。精神分裂症全基因组关联研究风险位点的精细定位基因在这些神经元和5/6层谷氨酸能神经元群体中的表达特异性明显高于其他基因。精神分裂症患者在PFC细胞表达的基因中罕见蛋白截短编码变异的发生率高于对照组。但是没有细胞群体显著富集超过这个背景率。
■我们确定了一组4层谷氨酸能PFC神经元可能特别受到精神分裂症常见变异遗传风险的影响，这可能会导致该病的丘脑皮质连通性紊乱。
前额叶皮层（PFC）与精神分裂症的潜在生物学密切相关。我们测试了PFC内的特定细胞群体是否优先表达增加疾病风险的基因。我们发现特定类型的PFC神经元显著表达与精神分裂症相关的基因，表明它参与了这种情况。
