Genetic Evidence for Protective and Risk Associations of Pathogen Antibodies with Brain Disorders

The role of infections in the etiology of brain disorders is increasingly recognized, yet causal relationships remain largely unresolved. Here, we perform a comprehensive Generalized Summary-data-based Mendelian Randomization (GSMR) analysis to systematically investigate the causal associations of genetically predicted antibody responses to 46 diverse pathogens with 13 major brain diseases. Our study reveals several novel and paradoxical causal links. We find strong genetic evidence for a protective effect of Herpes Simplex Virus 1 (HSV-1) seropositivity against Attention-Deficit/Hyperactivity Disorder (ADHD) and a protective association between Chlamydia trachomatis seropositivity and anxiety disorders. Furthermore, we uncover a dual role for Epstein-Barr virus (EBV) in multiple sclerosis (MS), where antibodies against the lytic-phase protein ZEBRA are protective, contrasting the established risk from EBNA-1 antibodies. These findings demonstrate that the nature of the host immune response, rather than infection status alone, is a critical determinant of brain health outcomes. This genetic atlas of pathogen-brain interactions challenges the conventional view of infections as purely detrimental and opens new avenues for developing immunomodulatory strategies for a range of brain disorders.