Tume Claire E, Chick Sophie L, Holmans Peter A, Rees Elliott, O'Donovan Michael C, Cameron Darren, Bray Nicholas J
Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, Wales, United Kingdom.
Neuroscience & Mental Health Innovation Institute, Cardiff University, Cardiff, Wales, United Kingdom.
Biol Psychiatry Glob Open Sci. 2024 Jun 8;4(5):100345. doi: 10.1016/j.bpsgos.2024.100345. eCollection 2024 Sep.
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.
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.
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.
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.
前额叶皮质（PFC）与精神分裂症的病理生理学密切相关。在此，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，以识别可能介导该疾病遗传易感性的组成细胞群体。
从一个包含人类PFC从妊娠到成年的84个细胞群体的单核RNA测序数据集中计算基因表达特异性值。在每种细胞类型具有高表达特异性的基因中测试精神分裂症常见变异易感性的富集以及罕见蛋白质截短编码变异的负担。我们还探讨了与相关神经元发育轨迹上的基因表达相关的精神分裂症常见变异关联。
精神分裂症的常见风险变异在婴儿期出现的一群成熟的第4层谷氨酸能神经元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易感性沿着该神经元群体的发育轨迹增加。在精神分裂症全基因组关联研究风险位点上精细定位的基因在这些神经元以及第5/6层谷氨酸能神经元群体中比其他基因具有显著更高的表达特异性。与对照个体相比，精神分裂症患者在PFC细胞表达的基因中具有罕见蛋白质截短编码变异的比例更高，但没有细胞群体在该背景率之上显著富集。
我们确定了一群第4层谷氨酸能PFC神经元，它们可能特别受精神分裂症常见变异遗传风险的影响，这可能导致该疾病中丘脑皮质连接的紊乱。
