Wu Yong, Yu Xiao-Lin, Xiao Xiao, Li Ming, Li Yi
Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
Mol Neurobiol. 2022 Jan;59(1):107-116. doi: 10.1007/s12035-021-02572-x. Epub 2021 Oct 9.
Genome-wide association studies (GWAS) have identified a large number of schizophrenia risk variants, and most of them are mapped to noncoding regions. By leveraging multiple joint-tissue gene expression data and GWAS data, we herein performed a transcriptome-wide association study (TWAS) and Mendelian randomization (MR) analysis and identified 144 genes whose mRNA levels were related to genetic risk of schizophrenia. Most of these genes exhibited diametrically opposite trends of expression in prenatal and postnatal brain tissues, despite that their expression levels in dorsolateral prefrontal cortex (DLPFC) tissues did not significantly differ between schizophrenics and healthy controls. We then found significant enrichment of these genes in dopamine-related pathways that were repeatedly implicated in schizophrenia pathogenesis and in the action of antipsychotic drugs. Gene expression analysis using single cell RNA-sequencing (scRNA-seq) data of mid-gestation fetal brains further revealed enrichment of these genes in glutamatergic excitatory neurons and cycling progenitors. These lines of evidence, in consistency with previous findings, confirmed the polygenic nature of schizophrenia and highlighted involvement of early neurodevelopment aberrations in this disorder. Further investigations using advanced algorithms in both bulk brain tissues and in single cells and at different developmental stages are necessary to characterize transcriptomic features of schizophrenia pathogenesis along brain development.
全基因组关联研究（GWAS）已经鉴定出大量精神分裂症风险变异，其中大多数被定位到非编码区域。通过利用多个联合组织基因表达数据和GWAS数据，我们在此进行了全转录组关联研究（TWAS）和孟德尔随机化（MR）分析，并鉴定出144个基因，其mRNA水平与精神分裂症的遗传风险相关。尽管这些基因在背外侧前额叶皮层（DLPFC）组织中的表达水平在精神分裂症患者和健康对照之间没有显著差异，但它们中的大多数在产前和产后脑组织中表现出完全相反的表达趋势。然后我们发现这些基因在与多巴胺相关的通路中显著富集，这些通路反复涉及精神分裂症的发病机制以及抗精神病药物的作用。使用妊娠中期胎儿脑的单细胞RNA测序（scRNA-seq）数据进行的基因表达分析进一步揭示了这些基因在谷氨酸能兴奋性神经元和循环祖细胞中的富集。这些证据与先前的发现一致，证实了精神分裂症的多基因性质，并突出了早期神经发育异常在该疾病中的作用。有必要在不同发育阶段的大块脑组织和单细胞中使用先进算法进行进一步研究，以表征精神分裂症发病机制沿脑发育的转录组特征。
