Journal Article

DZNE-2023-00984

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Docherty, A. R. ; Mullins, N. ; Ashley-Koch, A. E. ; Qin, X. ; Coleman, J. R. I. ; Shabalin, A. ; Kang, J. ; Murnyak, B. ; Wendt, F. ; Adams, M. ; Campos, A. I. ; DiBlasi, E. ; Fullerton, J. M. ; Kranzler, H. R. ; Bakian, A. V. ; Monson, E. T. ; Rentería, M. E. ; Walss-Bass, C. ; Andreassen, O. A. ; Behera, C. ; Bulik, C. M. ; Edenberg, H. J. ; Kessler, R. C. ; Mann, J. J. ; Nurnberger, J. I. ; Pistis, G. ; Streit, F. ; Ursano, R. J. ; Polimanti, R. ; Dennis, M. ; Garrett, M. ; Hair, L. ; Harvey, P. ; Hauser, E. R. ; Hauser, M. A. ; Huffman, J. ; Jacobson, D. ; Madduri, R. ; McMahon, B. ; Oslin, D. W. ; Trafton, J. ; Awasthi, S. ; Berrettini, W. H. ; Bohus, M. ; Chang, X. ; Chen, H.-C. ; Chen, W. J. ; Christensen, E. D. ; Crow, S. ; Duriez, P. ; Edwards, A. C. ; Fernández-Aranda, F. ; Galfalvy, H. ; Gandal, M. ; Gorwood, P. ; Guo, Y. ; Hafferty, J. D. ; Hakonarson, H. ; Halmi, K. A. ; Hishimoto, A. ; Jain, S. ; Jamain, S. ; Jiménez-Murcia, S. ; Johnson, C. ; Kaplan, A. S. ; Kaye, W. H. ; Keel, P. K. ; Kennedy, J. L. ; Kim, M. ; Klump, K. L. ; Levey, D. F. ; Li, D. ; Liao, S.-C. ; Lieb, K. ; Lilenfeld, L. ; Marshall, C. R. ; Mitchell, J. E. ; Okazaki, S. ; Otsuka, I. ; Pinto, D. ; Powers, A. ; Ramoz, N. ; Ripke, S. ; Roepke, S. ; Rozanov, V. ; Scherer, S. W. ; Schmahl, C. ; Sokolowski, M. ; Starnawska, A. ; Strober, M. ; Su, M.-H. ; Thornton, L. M. ; Treasure, J. ; Ware, E. B. ; Watson, H. J. ; Witt, S. H. ; Woodside, D. B. ; Yilmaz, Z. ; Zillich, L. ; Adolfsson, R. ; Agartz, I. ; Alda, M. ; Alfredsson, L. ; Appadurai, V. ; Artigas, M. S. ; Van der Auwera, S.DZNE* ; Azevedo, M. H. ; Bass, N. ; Bau, C. H. D. ; Baune, B. T. ; Bellivier, F. ; Berger, K. ; Biernacka, J. M. ; Bigdeli, T. B. ; Binder, E. B. ; Boehnke, M. ; Boks, M. P. ; Braff, D. L. ; Bryant, R. ; Budde, M. ; Byrne, E. M. ; Cahn, W. ; Castelao, E. ; Cervilla, J. A. ; Chaumette, B. ; Corvin, A. ; Craddock, N. ; Djurovic, S. ; Foo, J. C. ; Forstner, A. J. ; Frye, M. ; Gatt, J. M. ; Giegling, I. ; Grabe, H. J.DZNE* ; Green, M. J. ; Grevet, E. H. ; Grigoroiu-Serbanescu, M. ; Gutierrez, B. ; Guzman-Parra, J. ; Hamshere, M. L. ; Hartmann, A. M. ; Hauser, J. ; Heilmann-Heimbach, S. ; Hoffmann, P. ; Ising, M. ; Jones, I. ; Jones, L. A. ; Jonsson, L. ; Kahn, R. S. ; Kelsoe, J. R. ; Kendler, K. S. ; Kloiber, S. ; Koenen, K. C. ; Kogevinas, M. ; Krebs, M.-O. ; Landén, M. ; Leboyer, M. ; Lee, P. H. ; Levinson, D. F. ; Liao, C. ; Lissowska, J. ; Mayoral, F. ; McElroy, S. L. ; McGrath, P. ; McGuffin, P. ; McQuillin, A. ; Mehta, D. ; Melle, I. ; Mitchell, P. B. ; Molina, E. ; Morken, G. ; Nievergelt, C. ; Nöthen, M. M. ; O’Donovan, M. C. ; Ophoff, R. A. ; Owen, M. J. ; Pato, C. ; Pato, M. T. ; Penninx, B. W. J. H. ; Potash, J. B. ; Power, R. A. ; Preisig, M. ; Quested, D. ; Ramos-Quiroga, J. A. ; Reif, A. ; Ribasés, M. ; Richarte, V. ; Rietschel, M. ; Rivera, M. ; Roberts, A. ; Roberts, G. ; Rouleau, G. A. ; Rovaris, D. L. ; Sanders, A. R. ; Schofield, P. R. ; Schulze, T. G. ; Scott, L. J. ; Serretti, A. ; Shi, J. ; Sirignano, L. ; Sklar, P. ; Smeland, O. B. ; Smoller, J. W. ; Sonuga-Barke, E. J. S. ; Trzaskowski, M. ; Tsuang, M. T. ; Turecki, G. ; Vilar-Ribó, L. ; Vincent, J. B. ; Völzke, H. ; Walters, J. T. R. ; Weickert, C. S. ; Weickert, T. W. ; Weissman, M. M. ; Williams, L. M. ; Wray, N. R. ; Zai, C. C. ; Agerbo, E. ; Børglum, A. D. ; Breen, G. ; Demontis, D. ; Erlangsen, A. ; Gelernter, J. ; Glatt, S. J. ; Hougaard, D. M. ; Hwu, H.-G. ; Kuo, P.-H. ; Lewis, C. M. ; Li, Q. S. ; Liu, C.-M. ; Martin, N. G. ; McIntosh, A. M. ; Medland, S. E. ; Mors, O. ; Nordentoft, M. ; Olsen, C. M. ; Porteous, D. ; Smith, D. J. ; Stahl, E. A. ; Stein, M. B. ; Wasserman, D. ; Werge, T. ; Whiteman, D. C. ; Willour, V. ; Coon, H. ; Beckham, J. C. ; Kimbrel, N. A. ; Ruderfer, D. M.

2023
HighWire Press Stanford, Calif.

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Please use a persistent id in citations: doi:10.1176/appi.ajp.21121266

Abstract: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Keyword(s): Humans (MeSH) ; Genome-Wide Association Study (MeSH) ; Suicide, Attempted (MeSH) ; Depressive Disorder, Major: genetics (MeSH) ; Risk Factors (MeSH) ; Suicidal Ideation (MeSH) ; Polymorphism, Single Nucleotide: genetics (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Genetic Loci: genetics (MeSH) ; Biological Markers ; Depressive Disorders ; Genetics ; Schizophrenia Spectrum and Other Psychotic Disorders ; Self-Harm ; Suicide

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Contributing Institute(s):

1. Biomarkers of Dementia in the General Population (AG Grabe)
2. Translational Health Care Research (AG Hoffmann)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Current Contents - Social and Behavioral Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Social Sciences Citation Index ; Web of Science Core Collection

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