Genetic Relationships and Biological Pathways Underlying Suicidality and Comorbid Mental Disorders: A Comprehensive Cross-Phenotype Analysis

Document Type

Conference Proceeding

Publication Date

10-1-2024

Publication Title

European Neuropsychopharmacology

Abstract

BACKGROUND: The co-occurrence of mental disorders and suicidality are frequently seen in epidemiology. One explanation lies in shared genetic liabilities, hence we aimed to investigate the phenotypic and genetic associations between multiple mental disorders and different levels of suicidality.

METHODS: Using UK Biobank (UKB) European individual data, we first evaluated the phenotypic and polygenic relationships between 12 mental disorders and gradient scales of suicidality (spanning suicidal ideation, suicide attempts, and suicidal death). Second, we used existing genome-wide association study (GWAS) summary statistics to estimate genetic correlations and to identify pleiotropic genes using a combination of statistical genetics tools. Summary statistics were accessed from: 1) the Psychiatric Genomics Consortium (major depressive disorder [MDD], bipolar disorder [BD], anxiety disorders [ANX], obsessive-compulsive disorder [OCD], anorexia nervosa [AN], autism spectrum disorder [ASD], attention deficit hyperactivity disorder [ADHD], schizophrenia [SCZ], cannabis use disorder [CUD], and post-traumatic stress disorder [PTSD]), 2) the Million Veterans Program (alcohol use disorder [AUD] and opioid use disorder [OUD]), and 3) their joint analysis (suicidality). Third, using shared genetic liabilities as instrument, we evaluated evidence for causal relationship between mental disorders and suicidality by structural equation models and Mendelian randomizations. Last, we accessed the All of Us (AoU) diverse cohort data for replication in non-European populations.

RESULTS: For UKB, 150,861 eligible individuals were retained after standard GWAS quality control. Eight out 12 mental disorders (MDD, BD, ANX, AUD, OCD, AN, ASD and ADHD) showed both significant phenotypic and polygenic correlations with gradient suicidality (false discovery rate < 0.05). Among them, the impact of MDD and BD on suicidality were the most obvious (for MDD: OR=5.78 and 1.26 for phenotypic and polygenic level; for BD: OR=12.98 and 1.14 for phenotypic and polygenic level). Using GWAS summary statistics, we also observed positive global genetic correlations between those 8 mental disorders and suicidality (rg ranging from 0·25 to 0·68, p < 0.001). Across pairs of suicidality and mental disorders, we identified 23 functional genes (including novel ones like BPTF, NOL11 and CACNG5) shared by five or more pairs. These genes were significantly enriched in two Gene Ontology sets: developmental process and regulation of biological process. We also identified unique genes within each pair which were enriched in different pathways (e.g., glutamatergic synapse for suicidality-MDD, negative regulation of biological process for suicidality-BD, and actin cytoskeleton for suicidality-AUD). Causal models indicated potential causality from genetic diatheses of MDD, BD, AUD, ADHD, and ASD to risk of suicidality. Multiple cross-phenotype associations with suicidality were also replicated in AoU African and Asian populations (e.g., p < 0.05 for MDD and BD polygenic associations).

DISCUSSION: This study underscores the urgent need to address the shared and distinct genetic architecture of suicidality and related mental conditions. The combination of longitudinal population-level biobanks and disease-ascertained GWAS are warranted to enhance our understanding of their relationships. Our findings will provide insights into future suicide prevention and management among individuals with and without mental disorders.

DISCLOSURE: Nothing to disclose.

Volume

87

First Page

55

Last Page

55

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