Gui Jiawei, Chen Jiali, Wan Keqi, Liu Ying, Huang Kai, Zhu Xingen
The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, Jiangxi, China.
CNS Neurosci Ther. 2024 Dec;30(12):e70185. doi: 10.1111/cns.70185.
Previous research has demonstrated correlations between the complex types and functions of brain cells and the etiology of glioma. However, the causal relationship between gene expression regulation in specific brain cell types and glioma risk, along with its therapeutic implications, remains underexplored.
Utilizing brain cell type-specific cis-expression quantitative trait loci (cis-eQTLs) and glioma genome-wide association study (GWAS) datasets in conjunction with Mendelian randomization (MR) and colocalization analyses, we conducted a systematic investigation to determine whether an association exists between the gene expression of specific brain cell types and the susceptibility to glioma, including its subtypes. Additionally, the potential pathogenicity was explored utilizing mediation and bioinformatics analyses. This exploration ultimately led to the identification of a series of brain cell-specific therapeutic targets.
A total of 110 statistically significant and robust associations were identified through MR analysis, with most genes exhibiting causal effects exclusively in specific brain cell types or glioma subtypes. Bayesian colocalization analysis validated 36 associations involving 26 genes as potential brain cell-specific therapeutic targets. Mediation analysis revealed genes indirectly influencing glioma risk via telomere length. Bioinformatics analysis highlighted the involvement of these genes in glioma pathogenesis pathways and supported their enrichment in specific brain cell types.
This study, employing an integrated approach, demonstrated the genetic susceptibility between brain cell-specific gene expression and the risk of glioma and its subtypes. Its findings offer novel insights into glioma etiology and underscore potential therapeutic targets specific to brain cell types.
先前的研究已证明脑细胞的复杂类型和功能与胶质瘤的病因之间存在关联。然而，特定脑细胞类型中的基因表达调控与胶质瘤风险之间的因果关系及其治疗意义仍未得到充分探索。
利用脑细胞类型特异性顺式表达定量性状位点（cis-eQTLs）和胶质瘤全基因组关联研究（GWAS）数据集，结合孟德尔随机化（MR）和共定位分析，我们进行了一项系统研究，以确定特定脑细胞类型的基因表达与胶质瘤易感性（包括其亚型）之间是否存在关联。此外，利用中介分析和生物信息学分析探索了潜在的致病性。这一探索最终导致鉴定出一系列脑细胞特异性治疗靶点。
通过MR分析共鉴定出110个具有统计学意义且稳健的关联，大多数基因仅在特定脑细胞类型或胶质瘤亚型中表现出因果效应。贝叶斯共定位分析验证了36个涉及26个基因的关联，这些基因作为潜在的脑细胞特异性治疗靶点。中介分析揭示了基因通过端粒长度间接影响胶质瘤风险。生物信息学分析强调了这些基因参与胶质瘤发病机制途径，并支持它们在特定脑细胞类型中的富集。
本研究采用综合方法，证明了脑细胞特异性基因表达与胶质瘤及其亚型风险之间的遗传易感性。其研究结果为胶质瘤病因提供了新的见解，并强调了特定于脑细胞类型的潜在治疗靶点。
