{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:16:13Z","timestamp":1791980173964,"version":"4.4.0"},"reference-count":54,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2023,2,1]]},"abstract":"\n Importance<\/jats:title>\n Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To identify novel, replicable genomic risk loci for SITB.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This genome-wide association study included 633\u202f778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.<\/jats:p>\n <\/jats:sec>\n \n Main Outcome and Measures<\/jats:title>\n SITB.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 633\u202f778 US military veterans were included in the analysis (57\u202f152 [9%] female; 121\u202f118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452\u202f767 [71.4%] European ancestry, and 51\u202f608 [8.1%] Hispanic ancestry), including 121\u202f211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (\n P<\/jats:italic>\n \u2009&amp;lt;\u20095\u2009\u00d7\u200910\n \u22128<\/jats:sup>\n ) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in\n ESR1,<\/jats:italic>\n rs12808482 in\n DRD2,<\/jats:italic>\n rs77641763 in\n EXD3<\/jats:italic>\n , rs10671545 in\n DCC<\/jats:italic>\n , and rs36006172 in\n TRAF3.<\/jats:italic>\n Associations for\n FBXL19<\/jats:italic>\n and\n \n AC018880<\/jats:italic>\n <\/jats:ext-link>\n .2<\/jats:italic>\n were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including\n FURIN, TSNARE1,<\/jats:italic>\n and the\n NCAM1-TTC12-ANKK1-DRD2<\/jats:italic>\n gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry\u2013specific GWS loci were identified, 2 of which (\n POM121L2<\/jats:italic>\n and\n METTL15<\/jats:italic>\n \/\n LINC02758<\/jats:italic>\n ) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (\n PET112\/GATB<\/jats:italic>\n ) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (\n r<\/jats:italic>\n \u2009&amp;gt;\u20090.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for\n ESR1<\/jats:italic>\n ,\n DRD2<\/jats:italic>\n ,\n TRAF3<\/jats:italic>\n , and\n DCC<\/jats:italic>\n as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2022.3896","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T11:01:19Z","timestamp":1671015679000},"page":"135","source":"Crossref","is-referenced-by-count":60,"title":["Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans"],"prefix":"10.1001","volume":"80","author":[{"given":"Nathan A.","family":"Kimbrel","sequence":"first","affiliation":[{"name":"Durham Veterans Affairs Health Care System, Durham, North Carolina"},{"name":"Veterans Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina"},{"name":"Veterans Affairs Health Services Research and Development Center of Innovation to Accelerate Discovery and Practice Transformation, Durham, North Carolina"},{"name":"Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison E.","family":"Ashley-Koch","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute, Durham, North Carolina"},{"name":"Department of Medicine, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue J.","family":"Qin","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Health Care System, Durham, North Carolina"},{"name":"Duke Molecular Physiology Institute, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer H.","family":"Lindquist","sequence":"additional","affiliation":[{"name":"Veterans Affairs Health Services Research and Development Center of Innovation to Accelerate Discovery and Practice Transformation, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie E.","family":"Garrett","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle F.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Health Care System, Durham, North Carolina"},{"name":"Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren P.","family":"Hair","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Health Care System, Durham, North Carolina"},{"name":"Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Huffman","sequence":"additional","affiliation":[{"name":"Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Biosciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee"},{"name":"Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville"},{"name":"Department of Psychology, NeuroNet Research Center, University of Tennessee Knoxville"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi K.","family":"Madduri","sequence":"additional","affiliation":[{"name":"Consortium for Advanced Science and Engineering, The University of Chicago, Chicago, Illinois"},{"name":"Data Science and Learning Division, Argonne National Laboratory, Lemont, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodie A.","family":"Trafton","sequence":"additional","affiliation":[{"name":"Program Evaluation and Resource Center, Office of Mental Health and Suicide Prevention, Veterans Affairs Palo Alto Health Care System, Menlo Park, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Coon","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Huntsman Mental Health Institute, University of Utah School of Medicine, Salt Lake City"},{"name":"Biomedical Informatics, University of Utah School of Medicine, Salt Lake City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna R.","family":"Docherty","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Huntsman Mental Health Institute, University of Utah School of Medicine, Salt Lake City"},{"name":"Department of Psychiatry, Virginia Commonwealth University, Richmond"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh","family":"Mullins","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas M.","family":"Ruderfer","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee"},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"name":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D.","family":"Harvey","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida"},{"name":"Research Service, Bruce W. Carter VA Medical Center, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin H.","family":"McMahon","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Oslin","sequence":"additional","affiliation":[{"name":"Veterans Integrated Service Networks 4 Mental Illness Research, Education, and Clinical Center, Center of Excellence, Corporal Michael J Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania"},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean C.","family":"Beckham","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Health Care System, Durham, North Carolina"},{"name":"Veterans Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina"},{"name":"Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth R.","family":"Hauser","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Health Care System, Durham, North Carolina"},{"name":"Duke Molecular Physiology Institute, Durham, North Carolina"},{"name":"Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Hauser","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute, Durham, North Carolina"},{"name":"Department of Medicine, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khushbu","family":"Agarwal","sequence":"additional","affiliation":[{"name":"for the Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison E.","family":"Ashley-Koch","sequence":"additional","affiliation":[{"name":"for the Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the 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