美国西奈山伊坎医学院Panos Roussos团队取得一项新突破。他们的最新研究提出了人类大脑疾病的单核转录组关联研究。相关论文发表在2026年9月23日出版的《自然》杂志上。

常见脑部疾病造成了巨大的健康负担，但将其遗传风险定位到大脑中仍具挑战性。尽管全基因组关联研究已鉴定出许多与神经精神和神经退行性疾病相关的位点，但其中许多位点位于非编码区，影响特定细胞类型中的基因表达。传统的整体脑转录组分析通常集中于欧洲血统队列，对细胞多样性进行平均，掩盖了与遗传风险相关的基因表达变化。在此，研究人员利用多祖先PsychAD队列中背外侧前额叶皮层的单核基因表达谱，开发了跨主要脑细胞类型的遗传调控表达的转录组插补模型。将这些模型应用于神经精神和神经退行性疾病，揭示了数千个在整体组织分析中无法检测到的基因-性状关联，并将许多信号解析到离散的神经元、胶质细胞和免疫细胞群体。百万退伍军人计划中的跨祖先分析证实了这些关联，揭示了细胞类型特异性预测表达的多效性效应，并证明与性状相关的失调在不同祖先间是保守的，从而能够绘制因果基因和通路。总之，这些发现提供了一个细胞类型分辨且祖先感知的人类前额叶皮层遗传调控表达图谱，并说明了单核转录组学如何能够加强复杂脑部疾病的基因发现和治疗靶点优先排序。

附：英文原文

Title: Single-nucleus transcriptome-wide association study of human brain disorders

Author: Venkatesh, Sanan, Kosoy, Roman, Wu, Zhenyi, Anyfantakis, Marios, Dillard, Christian, N. M., Prashant, Burstein, David, Mathur, Deepika, Chatzinakos, Chris, Ajanaku, Bukola, Tsetsos, Fotis, Zeng, Biao, Gupta, Sonali, Bercovitch, Rachel, Hong, Aram, Casey, Clara, Alvia, Marcela, Shao, Zhiping, Argyriou, Stathis, Therrien, Karen, Bigdeli, Tim, Auluck, Pavan, Bennett, David A., Marenco, Stefano, Haroutunian, Vahram, Girdhar, Kiran, Bendl, Jaroslav, Lee, Donghoon, Fullard, John F., Hoffman, Gabriel E.

Issue&Volume: 2026-09-23

Abstract: Common brain disorders impose a substantial health burden, but localizing their genetic risk in the brain remains challenging1. Although genome-wide association studies have identified numerous loci associated with neuropsychiatric and neurodegenerative disorders, many of these loci lie in non-coding regions that influence gene expression in specific cell types2,3,4,5. Traditional bulk brain transcriptomic analyses, which often focus on European ancestry cohorts, average over cellular diversity, obscuring genetic risk-related changes in gene expression. Here we use single-nucleus gene expression profiles from the dorsolateral prefrontal cortex in the multi-ancestry PsychAD cohort to develop transcriptomic imputation models of genetically regulated expression across major brain cell types. Applying these models to neuropsychiatric and neurodegenerative disorders reveals thousands of gene–trait associations that are undetectable in bulk tissue analyses and resolves many signals to discrete neuronal, glial and immune cell populations. Cross-ancestry analyses in the Million Veteran Program confirm these associations, reveal pleiotropic effects of cell-type-specific predicted expression and demonstrate that trait-related dysregulation is conserved across ancestries, enabling mapping of causal genes and pathways. Together, these findings provide a cell-type-resolved and ancestry-aware atlas of genetically regulated expression in the human prefrontal cortex and illustrate how single-nucleus transcriptomics can sharpen gene discovery and therapeutic target prioritization for complex brain disorders.

DOI: 10.1038/s41586-026-10836-6

Source: https://www.nature.com/articles/s41586-026-10836-6