Background

While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition.

Methods

Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population.

Results

Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence, and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability.

Conclusions

We found evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neurons within the second-trimester fetal brain. Our study significantly advances the understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurologic disorders.

中文翻译：

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人类产前大脑 5 个区域的单核 RNA 测序表明发育中的神经元群体存在精神分裂症的遗传风险

背景

虽然各种证据支持精神分裂症的产前成分，但有关所涉及细胞群的数据很少。我们试图通过将单核 RNA 测序产生的细胞特异性基因表达测量与最近的大规模全基因组关联研究 (GWAS) 和外显子组测序数据相结合，来识别介导精神分裂症遗传风险的人类产前大脑细胞.

方法

对来自妊娠中期的 3 个胎儿的 5 个大脑区域（额叶皮层、神经节隆起、海马、丘脑和小脑）进行了单核 RNA 测序。精神分裂症常见变异遗传责任和罕见破坏性编码变异的富集与每个已识别细胞群内的基因表达特异性相关。

结果

常见的风险变异显着富集在对额叶皮层、神经节隆起和海马体中发育的神经元群具有高表达特异性的基因中。富集在很大程度上独立于成人大脑神经元群体中表达的基因，这些基因通过相同的方法与精神分裂症有关。在精神分裂症中含有过量罕见破坏性变异的基因对发育额叶皮层和海马体的谷氨酸能神经元具有更高的表达特异性，这些神经元也因常见的变异倾向而丰富。

结论

我们发现了产前神经元发育对精神分裂症遗传风险的明显贡献的证据，涉及妊娠中期胎儿大脑内发育中的特定神经元群体。我们的研究显着促进了对精神分裂症神经发育起源的理解，并提供了一种资源来调查其他精神和神经系统疾病的产前前因。