Dissecting the pleiotropic genetic architecture of suicide attempt, suicidal ideation, and thirteen correlated traits
Year: 2026
Type: article
Abstract: 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.
Source: European Neuropsychopharmacology
Authors: Alfonso Martone, Isabella Folego-Temoteo, Gabriel R. Fries, Anna R. Docherty, Allison E. Ashley-Koch, Alan Apter, Enrique Baca-García, Judit Balázs, Shira Barzilay, Julio Bobes, Raffaella Calati, Vladimir Carli, Philippe Courtet, Giuseppe Fanelli, Xenia Gonda, Iria Grande, Vasileios Masdrakis, Maurizio Pompili, Zoltán Rihmer, Dan Rujescu, Pilar A. Saiz, Anjali Sankar, Marco Sarchiapone, Alessandro Serretti, Marcus Sokolowski, Robertas Strumila, Lars-Håkan Thorell, Danuta Wasserman, Jerzy Wasserman, Abraham Weizman, Gil Zalsman, Cibele E. Bandeira, Eugenio H. Grevet, Claiton H.D. Bau, Janita Bralten, Chiara Fabbri, Alessandro Serretti, Giuseppe Fanelli, Diego L. Rovaris
Institutions: Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, Universidade de São Paulo, The University of Texas Health Science Center at Houston, Virginia Commonwealth University, University of Utah, Duke Medical Center, Tel Aviv University, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Eötvös Loránd University, University of Haifa, Universidad de Oviedo, University of Milano-Bicocca, Karolinska Institutet, Université de Montpellier, University of Udine, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Semmelweis University, Centro de Investigación Biomédica en Red de Salud Mental, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, National and Kapodistrian University of Athens, Sapienza University of Rome, Medical University of Vienna, Copenhagen University Hospital, Rigshospitalet, University of Molise, Università degli Studi di Enna Kore, Centre Hospitalier Universitaire de Montpellier, Linköping University, Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, University of Bologna
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $3,000
Funders: Università degli Studi di Milano, Fundação de Amparo à Pesquisa do Estado de São Paulo, Radboud Universiteit, Semmelweis Egyetem, Gentofte Hospital, Universität Wien, Linköpings Universitet, Istituto Superiore di Sanità, Karolinska Institutet, Sapienza Università di Roma, Tel Aviv University, Universidad Autónoma de Madrid, Rigshospitalet, National and Kapodistrian University of Athens, Centre Hospitalier Régional Universitaire de Montpellier, University of Haifa, Universitat de Barcelona, Medizinische Universität Wien, Università di Bologna, Radboud Universitair Medisch Centrum, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental, European College of Neuropsychopharmacology, Université de Montpellier, Università degli Studi di Udine, Eötvös Loránd Tudományegyetem, Centre Hospitalier Universitaire de Nîmes
OpenAlex ID: W4417137998