| Summary: | OBJECTIVES: To compare seroprevalence/characteristics of 49 autoantibodies (AB) against brain-antigens in neuropsychiatric patients and healthy individuals and elucidate predisposing factors. DESIGN/SETTING: Exploratory cross-sectional cohort study (N=7025). PARTICIPANTS: Subjects originate from the GRAS Data Collection of deeply phenotyped neuropsychiatric patients and healthy controls across Germany. OUTCOMES: Presence/characteristics of 49 brain-directed serum-AB, GWAS of NMDAR1-AB carriers, analysis of immune check-point genotypes, APOE4, neurotrauma. RESULTS: Analysis of N=7025 subjects (55.8% male; 41±16 years) reveals N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% confidence interval 1.015-1.022) emerges, but no disease association, neither general nor with neuropsychiatric disease subgroups. Males have higher AB seroprevalence (OR=1.303, 1.144-1.486). Overall immunoglobulin class distribution (N for IgM:462; IgA:487; IgG:477) and titer ranges (1:10-1:3200) are similar. Abundant are NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) is seen for most AB (amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65, Ma2, Yo, NF115, AP3B2, NF186, CNTN1, myelin, neurochondrin, flotillin1/2, CNTN2, IgLON5, AMPA, Sez6l2, recoverin, neurexin, mGluR1, ITPR1, GABA-b, LGI1, mGluR5, DRD2, CV2, Hu, Tr/DNER, AQP4, GluDR2, Zic-4, ERC1). Non-detectable are others (GABA-a, MBP, AT1A3, Ri, AGNA, CARPVIII, PCA-2, ANNA-3, DPPX, MAG). GWAS of NMDAR1-AB carriers reveals three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovers effects on humoral anti-brain autoimmunity (OR=1.55, 1.058-2.271) and disease likelihood (OR=1.43, 1.032-1.985). APOE4 carriers (∼19%) have lower seropositivity (OR=0.766, 0.625-0.933), likely because of AB-binding to brain tissue (ꞌimmunoprecipitationꞌ) upon chronic blood-brain-barrier leakiness, but no higher disease prevalence. Confirming preclinical findings, neurotrauma, inducing acute blood-brain-barrier disruption, predisposes to NMDAR1-AB (IgM: OR=1.599, 1.022-2.468). CONCLUSIONS: Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Important for clinical practice: Seroprevalence, immunoglobulin class, or titers do not predict disease.
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