Genome-wide pleiotropic analysis identifies shared genetic architecture within the cognition-immune nexus

Increasing evidence supports associations between cognitive function and autoimmune disorders, yet the underlying genetic mechanisms remain unclear. Using large-scale genome-wide association statistics for seven cognitive traits and fifteen autoimmune disorders, together with two independent cohorts comprising 522 healthy individuals and 80 patients with schizophrenia, we performed multi-level pleiotropic analyses. Genetic correlation analyses identified nine significant cognition-immune linkage pairs, whereas Mendelian randomization (MR) analyses suggested that these associations were largely driven by shared genetic architecture rather than causality. Using PLACO, colocalization analysis, and MAGMA analyses, we identified 46 pleiotropic loci and 169 pleiotropic genes across the linkage pairs. Polygenic risk scores derived from pleiotropic variants were associated with cognition in healthy adults and showed nominal associations in schizophrenia. Enrichment analyses linked these genes to cognition-immune-related tissues, pathways, and biological processes, while multi-trait colocalization highlighted CD33 as a potential key mediator. Finally, summary-based MR analyses of both pleiotropic genes and anti-inflammatory drug target genes highlighted AMT, CRAT, ERAP2, ERBB3, GNL3, IRF3, MST1R, RPS26, SH2B1, SULT1A1, SULT1A2, TMEM258, CYP2D6 and MAPK3 as promising therapeutic targets for both cognitive function and autoimmune disorders. This study delineates the shared genetic architecture underlying the cognition-immune nexus and identifies novel candidate targets, highlighting the value of integrative genetic approaches for advancing diagnosis and treatment.