Immunological Drivers and Potential Novel Drug Targets for Major Psychiatric, Neurodevelopmental, and Neurodegenerative Conditions

Abstract

Immune dysfunction is implicated in the aetiology of psychiatric, neurodevelopmental, and neurodegenerative conditions, but the issue of causality remains unclear impeding attempts to develop new interventions. We have tested evidence for causality for 735 immune response-related biomarkers on 7 neuropsychiatric conditions, using cutting-edge genomic causal inference methods (Mendelian randomization and genetic colocalization) applied to genomic data on protein and gene expression across blood and brain. We provide robust evidence of causality for 21 biomarkers, including two previously unreported (LATS1, and FCN1), confirming a role of both brain specific and systemic immune response in the pathogenesis of several neuropsychiatric conditions especially schizophrenia, Alzheimers disease, depression, and bipolar disorder. Furthermore, 18 of the identified biomarkers are therapeutically tractable, including ACE, TNFRSF17, and CD40, with drugs approved or in advanced clinical trials, offering a potential opportunity for drug repurposing.