Genetic and multi-omic prioritization implicates the CD33-SIGLEC locus in post-traumatic stress disorder

Genetic studies of post-traumatic stress disorder (PTSD) implicate immune regulation, yet linking peripheral immune-related proteins to brain molecular regulation and experimentally tractable targets remains challenging. Cellular and spatial genetic analyses were used to characterize the cellular and spatial genetic context of these traits. We then conducted bidirectional Mendelian randomization (MR) across 30 predefined Ig-like plasma proteins and 16 behavioral and neuropsychiatric traits. The forward MR screen identified four associations meeting the prespecified screening criteria, all of which underwent the same post-screening robustness assessment. CD33-PTSD showed the most consistent support across instrument definitions and applicable robust estimators and was therefore advanced as the prioritized candidate to regional genetic, brain molecular QTL, and functional analyses. Standard CD33 pQTL-PTSD colocalization did not support a simple shared single-variant model, while multi-signal analyses remained scientifically unresolved under the available LD reference. Meanwhile, plasma CD33 pQTL and cortical CD33 eQTL showed strong regional sharing (PP4=0.96468). Regional localization, cross-analysis candidate selection, and functional annotation further suggested a complex regulatory context across the CD33-SIGLEC region. Among 284 compounds with prior CD33 binding evidence that entered structure-assisted screening, 11 were retained as candidates for experimental follow-up. Overall, CD33-PTSD was the prioritized association identified by our screening; subsequent regional genetic, brain molecular QTL, and functional annotation analyses further delineated the complex regulatory context of the CD33- SIGLEC locus, while the CD33-centered structure-assisted exploration yielded 11 compound candidates for subsequent experimental validation.