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 understood underlying genetic and molecular mechanisms. We investigated the shared genetic architecture of SA and SI with 13 genetically correlated psychiatric, behavioural, and somatic phenotypes using summary statistics from 15 genome-wide association studies (N=46,350-975,353). Local Analysis of [co]Variant Association (LAVA) quantified locus-specific genetic covariance, while conjunctional false discovery rate (conjFDR) identified pairwise jointly associated genetic variants. Functional annotation and enrichment analyses characterised pathways and tissue-expression patterns. LAVA identified 16 loci with significant local correlations, mapping to 493 unique genes. After conditioning on depression 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 to 798 unique genes, enriched for pathways involving cell adhesion, neurogenesis, signal transduction, chromatin regulation, immune processes, and protein secretion. Stratified analyses showed that SA pairs were enriched for gene sets related to brain morphology, cognition, and sleep regulation, whereas SI pairs for gene sets related to neuroticism, body mass index, and gastrointestinal traits. Shared loci displayed mixed 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.

Duke Scholars

Author Allison Elizabeth Ashley-Koch Medicine, Nephrology