44. IMMUNE RISK AND SUICIDE ATTEMPT: CLINICAL AND POLYGENIC EVIDENCE FROM ALL OF US

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

Eur Neuropsychopharmacol

Abstract

Background: Suicide is a global public health concern with complex environmental, social, and biological underpinnings. Increasing clinical evidence suggests that immune system dysregulation may contribute to suicidality, with autoimmune diseases frequently observed among individuals with suicide attempt. Inflammatory biomarkers have also been implicated in suicide risk and prediction. However, whether polygenic susceptibility contributes to the relationship between autoimmune diseases and suicidality remains largely unclear. Methods: Based on data from 633,547 individuals in the All of Us Research Program (AoU, controlled tier v8), we first examined the prevalence of 10 autoimmune diseases in SA individuals, including systemic lupus erythematosus (SLE), rheumatoid arthritis and (RA), type 1 diabetes mellitus (T1D). Logistic regression models were used to estimate phenotypic associations between suicide attempt (SA) and autoimmune diseases. To assess genetic liability, polygenic risk scores (PRS) for autoimmune traits were calculated using PRS-CS based on publicly available GWAS summary statistics. Associations between PRS and SA were tested using logistic regression, adjusting for age, sex, and top five genetic principal components. We also explored whether autoimmune polygenic risk contributes to the progression from suicidal ideation (SI) to SA. Results: Among 5,898 individuals with a history of SA (mean age 50.2 years; 52.98% female), 11.05% had at least one autoimmune disease. The most common conditions were RA (6.24%), T1D (5.60%), and psoriasis (3.73%). Bidirectional phenotypic associations were observed between SA and most autoimmune diseases, with odds ratios ranging from 1.89 (RA; 95% CI: 1.69–2.11) to 2.82 (SLE; 95% CI: 2.40–3.31). At the genetic level, SA was significantly associated with higher PRS for T1D (OR = 1.12, 95% CI: 1.07–1.16), SLE (OR = 1.09, 95% CI: 1.04–1.13), and RA (OR = 1.06, 95% CI: 1.02–1.11). Additional associations were observed for psoriasis, atopic dermatitis, and Crohn's disease. These effects were modest in magnitude but consistent and statistically robust. Among individuals with SI, while none reached statistical significance, all autoimmune PRS showed directionally consistent positive associations with progression to suicide attempt (ORs ranging from 1.02 to 1.05). Discussion: The elevated burden of autoimmune diseases among individuals with suicide attempt, combined with increased polygenic liability to immune-related traits, suggests a potential immunogenetic component in suicide risk. While individual genetic effects were modest, their consistency across multiple autoimmune conditions and alignment with clinical associations support the hypothesis that immune dysregulation may contribute to suicidal behavior. Autoimmune PRS also showed directionally positive associations with the transition from suicidal ideation to suicide attempt, indicating a potential role in the ideation-to-action process. These findings complement emerging literature on neuroinflammation and suicidality and highlight the value of investigating immune-related mechanisms in suicide research. Ongoing work will explore pathway-specific polygenic profiles to identify immune-related biological mechanisms underlying suicide pathophysiology. This mechanism-based new evidence will assist new strategy development (via earlier identification and prediction) for future suicide prevention and mental health services.

Volume

99

First Page

76

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