Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.
Single-Nuclei RNA Sequencing of 5 Regions of the Human Prenatal Brain Implicates Developing Neuron Populations in Genetic Risk for Schizophrenia.
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DOI：
10.1016/j.biopsych.2022.06.033
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发表时间：
2023-01-15
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然有各种证据支持精神分裂症的产前成分，但关于所涉及的细胞群的数据很少。我们试图通过整合单核RNA测序产生的细胞特异性基因表达测量值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来确定人类产前脑细胞介导精神分裂症的遗传风险。对妊娠中期3个胎儿的5个脑区（额叶皮质、神经节隆起、海马、丘脑和小脑）进行单核RNA测序。精神分裂症常见变异遗传易感性和罕见破坏性编码变异的富集与每个鉴定的细胞群体内的基因表达特异性有关。常见的风险变异显著地富集在对额叶皮层、神经节隆起和海马内的发育中的神经元群体具有高表达特异性的基因内。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额叶皮层和海马的发育中的海马能神经元具有更高的表达特异性，这些神经元也富含常见的变异倾向。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，涉及中期胎儿大脑中发育神经元的特定群体。我们的研究显著地推进了对精神分裂症的神经发育起源的理解，并为调查其他精神和神经系统疾病的产前前因提供了资源。
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. 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. 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. 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.
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影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
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通讯作者：
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Mill J
影响因子：
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作者：
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