Causal Association Between Immune Cell Traits and Risk of Multiple Malignant and Nonmalignant CNS Diseases: A Mendelian Randomization and Single‐Cell Transcriptomic Analysis

Background The influence of immune cell traits (ICTs) on the onset of multiple brain diseases has been previously investigated; however, it is limited by the sample size or colocalization evidence. Besides, the impact remains inconclusive. Methods We performed a Mendelian randomization (MR) study to elucidate the causal correlation between significant ICTs and diverse brain disorders and explored the biomarkers linked to glioblastoma (GBM), a form of solid tumor, by integrating expression quantitative trait locus (eQTL) and single‐cell RNA sequencing (scRNA‐seq) analyses. The nonnegative matrix factorization (NMF) method was utilized to reclassify malignant cells into distinct cell states. Related functional analyses at the scRNA‐seq level were also performed. Results We examined 731 ICTs across 13 brain disorders; impacts from these ICTs varied a lot across different brain diseases. Such ICTs mainly involved T/natural killer (NK) cell activation, B cell differentiation, and myeloid cell suppression or activation. Pleiotropy or heterogeneity in current results has been checked and excluded via sensitivity analyses. Specifically, colocalization analyses demonstrated protective roles of distinct ICTs in T/B/NK cell panels for amyotrophic lateral sclerosis (ALS) and GBM, while myeloid and human leukocyte antigen (HLA)‐associated traits were associated with increased risk of Alzheimer's disease (AD), and then two memory cell traits were linked to the increased risk of major depressive disease (MDD). By NMF, we identified six distinct cell states within GBM cells. Furthermore, we established an eight‐marker glioblastoma risk signature (GBRS) using scRNA‐seq and eQTL data, with higher GBRS scores observed in the NFkB cluster and EGFR cluster, indicating their highlighted aggression among malignant cells. Epigallocatechin gallate could be an effective treatment candidate targeting the EGFR cluster via markers of SQLE and VCP . Conclusion Our findings identified causal effects of distinct ICTs on both malignant and nonmalignant brain diseases and underscored the pivotal role of neuroinflammation in their etiology. With combined evidence from eQTL and scRNA‐seq, GBM could be better characterized and managed.