美国哥伦比亚大学Philip L. De Jager及其研究组揭示了阿尔茨海默病患者大脑中基因变异对细胞亚型特异性的影响。这一研究成果于2024年3月21日发表在国际学术期刊《自然-遗传学》上。

研究人员从424个高龄个体的新皮质中获得了单核RNA测序数据。研究利用150万个转录组数据评估了遗传变异对7种细胞类型和64种细胞亚型顺式RNA表达（顺式表达定量性状位点）的影响。这项工作在细胞类型水平上发现了10,004个电子基因，在细胞亚型水平上发现了8,099个电子基因。许多电子基因只在细胞亚型中表达。

一种新的变异只影响APOE在小胶质细胞中的表达，在对APOEε4进行校对后，研究发现它与脑淀粉样血管病变相关，但与阿尔茨海默病的病理变化无关，为这两种病理变化提供了机理上的启发。

此外，只有TMEM106B变异会影响细胞亚型的比例。将这些结果与全基因组关联研究相结合，揭示了阿尔茨海默病、精神分裂症、教育程度和帕金森病位点中目标细胞类型和可能的致病基因。

据了解，遗传变异与脑细胞类型和亚型基因表达之间的关系仍未得到充分研究。

附：英文原文

Title: Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain

Author: Fujita, Masashi, Gao, Zongmei, Zeng, Lu, McCabe, Cristin, White, Charles C., Ng, Bernard, Green, Gilad Sahar, Rozenblatt-Rosen, Orit, Phillips, Devan, Amir-Zilberstein, Liat, Lee, Hyo, Pearse, Richard V., Khan, Atlas, Vardarajan, Badri N., Kiryluk, Krzysztof, Ye, Chun Jimmie, Klein, Hans-Ulrich, Wang, Gao, Regev, Aviv, Habib, Naomi, Schneider, Julie A., Wang, Yanling, Young-Pearse, Tracy, Mostafavi, Sara, Bennett, David A., Menon, Vilas, De Jager, Philip L.

Issue&Volume: 2024-03-21

Abstract: The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer’s disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer’s disease, schizophrenia, educational attainment and Parkinson’s disease loci.

DOI: 10.1038/s41588-024-01685-y

Source: https://www.nature.com/articles/s41588-024-01685-y