Single-cell transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-mediated mechanisms and drug targets for neuropsychiatric disorders

Many neuropsychiatric disorders are driven by immunity, but the specific underlying mechanisms and how best to exploit them for therapy remain elusive. Here we combine single-cell transcriptomics of dynamic T cell activation states, identification of expression quantitative trait loci, and Mendelian randomization and colocalization analyses to identify causative genes, pathways, and drug targets in Alzheimer's disease (AD) and major depressive disorder (MDD). During CD4⁺ T cell activation, we identify 73 and 156 putative causal genes for AD and MDD, respectively, with over 90% validating in independent datasets. Twenty-nine (13%) identified genes exhibit CD4⁺ T cell specificity and 34 (15%) show temporal causal patterns. Notably, genes with time-specific effects are 7.4- and 6.2-times more likely to exhibit genetic evidence for AD and MDD, respectively. Twenty-one prioritized genes, including RAC1 and PARP1, are targets for potential drug repurposing. This study provides new evidence for the role of immune-mediated mechanisms in neuropsychiatric disorders and prioritizes drug targets.