GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Anna R. Docherty*, Niamh Mullins, Allison E. Ashley-Koch, Xuejun Qin, Jonathan R.I. Coleman, Andrey Shabalin, Joo Eun Kang, Balasz Murnyak, Frank Wendt, Mark Adams, Adrian I. Campos, Emily DiBlasi, Janice M. Fullerton, Henry R. Kranzler, Amanda V. Bakian, Eric T. Monson, Miguel E. Rentería, Consuelo Walss-Bass, Ole A. Andreassen, Chittaranjan BeheraCynthia M. Bulik, Howard J. Edenberg, Ronald C. Kessler, J. John Mann, John I. Nurnberger, Giorgio Pistis, Fabian Streit, Robert J. Ursano, Renato Polimanti, Michelle Dennis, Melanie Garrett, Lauren Hair, Philip Harvey, Elizabeth R. Hauser, Michael A. Hauser, Jennifer Huffman, Daniel Jacobson, Ravi Madduri, Benjamin McMahon, David W. Oslin, Jodie Trafton, Swapnil Awasthi, Wade H. Berrettini, Martin Bohus, Xiao Chang, Hsi Chung Chen, Wei J. Chen, Erik D.M.D. Christensen, Scott Crow, Philibert Duriez, Alexis C. Edwards, Fernando Fernández-Aranda, Hanga Galfalvy, Michael Gandal, Philip Gorwood, Yiran Guo, Jonathan D. Hafferty, Hakon Hakonarson, Katherine A. Halmi, Akitoyo Hishimoto, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Minsoo Kim, Kelly L. Klump, Daniel F. Levey, Dong Li, Shih Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Christian R. Marshall, James E. Mitchell, Satoshi Okazaki, Ikuo Otsuka, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stephan Ripke, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Anna Starnawska, Michael Strober, Mei Hsin Su, Laura M. Thornton, Janet Treasure, Erin B. Ware, Hunna J. Watson, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Vivek Appadurai, María Soler Artigas, Sandra Van Der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Aiden Corvin, Nicholas Craddock, Srdjan Djurovic, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Justine M. Gatt, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Marian L. Hamshere, Annette M. Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Marie Odile Krebs, Mikael Landén, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Divya Mehta, Ingrid Melle, Philip B. Mitchell, Esther Molina, Gunnar Morken, Caroline Nievergelt, Markus M. Nöthen, Michael C. O'Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, MacIej Trzaskowski, Ming T. Tsuang, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Esben Agerbo, Anders D. Børglum, Gerome Breen, Ditte Demontis, Annette Erlangsen, Joel Gelernter, Stephen J. Glatt, David M. Hougaard, Hai Gwo Hwu, Po Hsiu Kuo, Cathryn M. Lewis, Qingqin S. Li, Chih Min Liu, Nicholas G. Martin, Andrew M. McIntosh, Sarah E. Medland, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Danuta Wasserman, Thomas Werge, David C. Whiteman, Virginia Willour, Hilary Coon, Jean C. Beckham, Nathan A. Kimbrel, Douglas M. Ruderfer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)723-738
Number of pages16
JournalAmerican Journal of Psychiatry
Volume180
Issue number10
DOIs
Publication statusPublished - 2023

Fingerprint

Dive into the research topics of 'GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors'. Together they form a unique fingerprint.

Cite this