In-Depth characterization of the shared genetic architecture of suicide attempts with other major psychiatric...

Suicide is a significant public health problem that usually co-occurs with major psychiatric disorders. Suicidal behaviors have heritability of 30-50%, and the largest genome-wide association studies identified 12 loci linked to suicide attempts (SA). These findings indicate shared genetic architecture among SA and psychiatric disorders. We analyzed public GWAS summary statistics of SA, major depressive disorder (MDD), bipolar disorder (BIP), schizophrenia (SCZ), and attention deficit hyperactivity disorder (ADHD) to quantify genetic overlap using statistical genetics methods: MiXeR for polygenic overlap, LAVA for locus-specific genetic correlations, and HyPrColoc for multi-trait colocalization. MTAG and conditional false discovery rate (condFDR) identified SA- associated loci, while conjunctional false discovery rate (conjFDR) identified shared loci with psychiatric disorders. Additionally, we used polygenic risk scores (PRS) calculated in the UK Biobank to validate associations between genetic liabilities of psychiatric disorders and SA. SA involve approximately 6.9k (SD = 1.5k) risk variants with substantial overlap between psychiatric disorders, ranging from 53.2% with SCZ to 82.1% with BIP. Using MTAG, condFDR, and conjFDR, we identified 14 and 48 novel risk loci for SA, respectively. Through conjFDR, we identified 78 loci associated with SA and major psychiatric disorders, including one locus shared across all five traits. Genes linked to SA were enriched in synaptic components and signaling pathways. Despite significant genetic overlap, the SA PRS was the single strongest predictor of SA, followed by the MDD and ADHD PRS. The genetic overlap reflects potential common comorbidities complicating the identification of biological processes unique to SA, instead reflecting a complex genetic framework shared with psychiatric disorders.