T4. SHARED GENETIC ARCHITECTURE OF ANXIETY AND IMMUNE-MEDIATED CONDITIONS: FROM LATENT FACTORS TO FUNCTIONAL PATHWAYS

Background Anxiety disorders frequently co-occur with immune-mediated conditions, ranging from autoimmune and allergic disorders to increased vulnerability to infections. While growing attention has been paid to the shared genetic links between anxiety and immune conditions, existing studies have focused on individual conditions rather than characterizing genetic overlap across immune domains. It therefore remains unknown whether this reflects a common transdiagnostic signal or distinct subtype-specific pathways. Methods Using the latest available GWAS summary statistics, including the most recent anxiety GWAS from the PGC, we analysed genetic overlap between anxiety and 14 immune traits across three domains: autoimmune, atopic, and infection susceptibility. Genomic SEM, informed by exploratory and confirmatory factor analyses, was applied to construct latent genetic factors capturing shared variance across immune traits. Genetic correlations between anxiety and each latent factor were estimated within the Genomic SEM framework, and anxiety was then regressed onto these factors. Multivariate GWAS of second-order factors representing the shared genetic architecture between each immune factor and anxiety were conducted using userGWAS. Functional annotation used FUMA (positional, eQTL, and chromatin interaction mapping), MAGMA (gene-based, gene-set, and gene-property analyses), and then g:Profiler for functional enrichment analyses of the identified genes. Results Three latent immune factors were identified: autoimmune (type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and autoimmune hypothyroidism), atopic (asthma, allergic rhinitis, and atopic dermatitis), and infectious (COVID-19, pneumonia, skin infections, intestinal infections, and asthma). Psoriasis, inflammatory bowel disease, and multiple sclerosis did not load onto any factor, while asthma cross-loaded onto two factors. All three immune factors showed significant genetic correlations with anxiety, with the infectious factor showing the strongest association (autoimmune rg = 0.220, SE = 0.025, p = 2.64 × 10-18; atopic rg = 0.156, SE = 0.034, p = 3.99 × 10-6; infectious rg = 0.535, SE = 0.039, p = 1.52 × 10-42). When jointly modelled, only the infectious factor was independently associated with anxiety (β = 0.561, SE = 0.06, p = 7.82 × 10-21), accounting for 29% of anxiety SNP-heritability. Gene annotation identified 56, 77, and 69 genes for the anxiety-autoimmune, anxiety-atopic, and anxiety-infectious second-order factors, with 33 genes shared across all three. MAGMA analyses identified 80, 90, and 89 genomic risk loci mapping to 102, 138, and 137 genes, of which 39, 53, and 52 were corroborated by SNP annotation. Shared genes were enriched for synaptic and platelet alpha granule lumen cellular components. Factor-specific enrichment revealed acute-phase response pathways for the anxiety-atopic factor, and complement activation and long-term synaptic depression pathways for the anxiety-infectious factor. Gene-property analyses showed preferential brain and pituitary gland expression across factors. Discussion These findings reveal common and group-specific shared genetic architecture between anxiety and immune-mediated diseases, with the infectious factor showing the strongest overlap with anxiety. Shared and factor-specific signals tied to neuroendocrine and inflammatory processes offer novel targets for mechanistic investigation of anxiety-immune comorbidities.