Dissecting the pleiotropic genetic architecture of suicide attempt, suicidal ideation, and thirteen correlated traits

Suicide attempts (SA) and suicidal ideation (SI) are major public health concerns with incompletely defined biology. We investigated shared genetic architecture between SA or SI and thirteen correlated phenotypes using genome-wide association study summary statistics from 46,350 to 975,353 individuals. Local Analysis of [co]Variant Association (LAVA) identified locus-specific genetic covariance, while conjunctional false discovery rate (conjFDR) analyses detected single-nucleotide polymorphysms jointly associated with suicide phenotypes and external traits. Functional annotation and enrichment analyses characterised pathways and tissue-specific expression. LAVA identified sixteen loci with significant local correlations, mapping to 493 genes. After conditioning on major depressive disorder and post-traumatic stress disorder, several locus-trait-pair correlations remained significant, including SI-ADHD, whose mapped genes were differentially expressed in hypothalamus, cortical regions, and peripheral tissues. Correlated loci implicated ion transport and transcriptional regulation. ConjFDR identified shared loci mapping 798 genes. These genes showed enrichment for pathways related to cell adhesion, neurogenesis, signal transduction, chromatin regulation, immune processes, and protein secretion. Stratified analyses showed SA-based pairs enriched for gene sets related to brain morphology, cognition, and sleep regulation, whereas SI-based pairs for neuroticism, body mass index, and gastrointestinal traits. Across pairs, shared loci displayed both concordant and discordant effect directions. Both SA and SI were enriched for gene sets involving glycine, serine, and threonine metabolism, systemic lupus erythematosus, and DNA damage- and telomere stress-induced senescence. Recurrently mapped genes exhibited region- and developmental stage-specific brain expression. These findings refine the genetic architecture of suicide and implicate neurodevelopmental, immune, metabolic, and chromatin-related mechanisms in suicidal thoughts and behaviours.