美国利伯大脑发展研究所Thomas M. Hyde、Andrew E. Jaffe以及美国阿斯特拉研究所Mitsuyuki Matsumoto研究团队合作取得一项新突破。他们分析了人类海马中齿状回的颗粒细胞层（DG-GCL）的基因表达，揭示了对精神分裂症及其遗传风险的见解。相关论文发表在2020年3月16日出版的《自然-神经科学》杂志上。

他们在大量海马数据中发现了缺失的或不均一的DG-GCL，鉴定了普遍存在的富含细胞类型的衰老和遗传效应。在DG-GCL中鉴定出的约900万个表达定量性状基因座中，在海马体中15%未检测到，包括15个精神分裂症风险变异。他们从DG-GCL创建了转录组范围的关联研究遗传权重，该遗传权重确定了大量海马体在转录组范围的关联研究中未发现的许多精神分裂症相关的遗传信号，包括GRM3和CACNA1C。这些结果凸显了有针对性的采样策略（如LCM）和人脑中的完整匀浆和单核方法所提供的更高的生物分辨率。

据悉，特定的细胞群可能对精神分裂症有独特的贡献，但在匀浆组织的研究中可能会遗漏。在这里，使用激光捕获显微切割，然后进行RNA测序（LCM-seq），以转录组分析人类DG-GCL，并将这些数据与从大量海马匀浆获得的数据进行对比。

附：英文原文

Title: Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk

Author: Andrew E. Jaffe, Daniel J. Hoeppner, Takeshi Saito, Lou Blanpain, Joy Ukaigwe, Emily E. Burke, Leonardo Collado-Torres, Ran Tao, Katsunori Tajinda, Kristen R. Maynard, Matthew N. Tran, Keri Martinowich, Amy Deep-Soboslay, Joo Heon Shin, Joel E. Kleinman, Daniel R. Weinberger, Mitsuyuki Matsumoto, Thomas M. Hyde

Issue&Volume: 2020-03-16

Abstract: Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C. These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain.

DOI: 10.1038/s41593-020-0604-z

Source: https://www.nature.com/articles/s41593-020-0604-z