@article{f6bd3cd505d64a8789184e912a091e82,
title = "GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors",
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.",
author = "{MVP Suicide Exemplar Workgroup} and {Psychiat Genomics Consortium} and {German Borderline Genomics Consortium} and Docherty, {Anna R.} and Niamh Mullins and Ashley-Koch, {Allison E.} and Xuejun Qin and Coleman, {Jonathan R.I.} and Andrey Shabalin and Kang, {Joo Eun} and Balasz Murnyak and Frank Wendt and Mark Adams and Campos, {Adrian I.} and Emily DiBlasi and Fullerton, {Janice M.} and Kranzler, {Henry R.} and Bakian, {Amanda V.} and Monson, {Eric T.} and Renter{\'i}a, {Miguel E.} and Consuelo Walss-Bass and Andreassen, {Ole A.} and Chittaranjan Behera and Bulik, {Cynthia M.} and Edenberg, {Howard J.} and Kessler, {Ronald C.} and {John Mann}, J. and Nurnberger, {John I.} and Giorgio Pistis and Fabian Streit and Ursano, {Robert J.} and Renato Polimanti and Michelle Dennis and Melanie Garrett and Lauren Hair and Philip Harvey and Hauser, {Elizabeth R.} and Hauser, {Michael A.} and Jennifer Huffman and Daniel Jacobson and Ravi Madduri and Benjamin McMahon and Oslin, {David W.} and Jodie Trafton and Swapnil Awasthi and Berrettini, {Wade H.} and Martin Bohus and Xiao Chang and Chen, {Hsi Chung} and Chen, {Wei J.} and Christensen, {Erik D.M.D.} and Scott Crow and Philibert Duriez and Edwards, {Alexis C.} and Fernando Fern{\'a}ndez-Aranda and Hanga Galfalvy and Michael Gandal and Philip Gorwood and Yiran Guo and Hafferty, {Jonathan D.} and Hakon Hakonarson and Halmi, {Katherine A.} and Akitoyo Hishimoto and Sonia Jain and St{\'e}phane Jamain and Susana Jim{\'e}nez-Murcia and Craig Johnson and Kaplan, {Allan S.} and Kaye, {Walter H.} and Keel, {Pamela K.} and Kennedy, {James L.} and Minsoo Kim and Klump, {Kelly L.} and Levey, {Daniel F.} and Dong Li and Liao, {Shih Cheng} and Klaus Lieb and Lisa Lilenfeld and Marshall, {Christian R.} and Mitchell, {James E.} and Satoshi Okazaki and Ikuo Otsuka and Dalila Pinto and Abigail Powers and Nicolas Ramoz and Stephan Ripke and Stefan Roepke and Vsevolod Rozanov and Scherer, {Stephen W.} and Christian Schmahl and Marcus Sokolowski and Anna Starnawska and Michael Strober and Su, {Mei Hsin} and Thornton, {Laura M.} and Janet Treasure and Ware, {Erin B.} and Watson, {Hunna J.} and Witt, {Stephanie H.} and {Blake Woodside}, D. and Zeynep Yilmaz and Lea Zillich and Rolf Adolfsson and Ingrid Agartz and Martin Alda and Lars Alfredsson and Vivek Appadurai and Artigas, {Mar{\'i}a Soler} and {Van Der Auwera}, Sandra and {Helena Azevedo}, M. and Nicholas Bass and Bau, {Claiton H.D.} and Baune, {Bernhard T.} and Frank Bellivier and Klaus Berger and Biernacka, {Joanna M.} and Bigdeli, {Tim B.} and Binder, {Elisabeth B.} and Michael Boehnke and Boks, {Marco P.} and Braff, {David L.} and Richard Bryant and Monika Budde and Byrne, {Enda M.} and Wiepke Cahn and Enrique Castelao and Cervilla, {Jorge A.} and Boris Chaumette and Aiden Corvin and Nicholas Craddock and Srdjan Djurovic and Foo, {Jerome C.} and Forstner, {Andreas J.} and Mark Frye and Gatt, {Justine M.} and Ina Giegling and Grabe, {Hans J.} and Green, {Melissa J.} and Grevet, {Eugenio H.} and Maria Grigoroiu-Serbanescu and Blanca Gutierrez and Jose Guzman-Parra and Hamshere, {Marian L.} and Hartmann, {Annette M.} and Joanna Hauser and Stefanie Heilmann-Heimbach and Per Hoffmann and Marcus Ising and Ian Jones and Jones, {Lisa A.} and Lina Jonsson and Kahn, {Ren{\'e} S.} and Kelsoe, {John R.} and Kendler, {Kenneth S.} and Stefan Kloiber and Koenen, {Karestan C.} and Manolis Kogevinas and Krebs, {Marie Odile} and Mikael Land{\'e}n and Marion Leboyer and Lee, {Phil H.} and Levinson, {Douglas F.} and Calwing Liao and Jolanta Lissowska and Fermin Mayoral and McElroy, {Susan L.} and Patrick McGrath and Peter McGuffin and Andrew McQuillin and Divya Mehta and Ingrid Melle and Mitchell, {Philip B.} and Esther Molina and Gunnar Morken and Caroline Nievergelt and N{\"o}then, {Markus M.} and O'Donovan, {Michael C.} and Ophoff, {Roel A.} and Owen, {Michael J.} and Carlos Pato and Pato, {Michele T.} and Penninx, {Brenda W.J.H.} and Potash, {James B.} and Power, {Robert A.} and Martin Preisig and Digby Quested and Ramos-Quiroga, {Josep Antoni} and Andreas Reif and Marta Ribas{\'e}s and Vanesa Richarte and Marcella Rietschel and Margarita Rivera and Andrea Roberts and Gloria Roberts and Rouleau, {Guy A.} and Rovaris, {Diego L.} and Sanders, {Alan R.} and Schofield, {Peter R.} and Schulze, {Thomas G.} and Scott, {Laura J.} and Alessandro Serretti and Jianxin Shi and Lea Sirignano and Pamela Sklar and Smeland, {Olav B.} and Smoller, {Jordan W.} and Sonuga-Barke, {Edmund J.S.} and MacIej Trzaskowski and Tsuang, {Ming T.} and Gustavo Turecki and Laura Vilar-Rib{\'o} and Vincent, {John B.} and Henry V{\"o}lzke and Walters, {James T.R.} and Weickert, {Cynthia Shannon} and Weickert, {Thomas W.} and Weissman, {Myrna M.} and Williams, {Leanne M.} and Wray, {Naomi R.} and Zai, {Clement C.} and Esben Agerbo and B{\o}rglum, {Anders D.} and Gerome Breen and Ditte Demontis and Annette Erlangsen and Joel Gelernter and Glatt, {Stephen J.} and Hougaard, {David M.} and Hwu, {Hai Gwo} and Kuo, {Po Hsiu} and Lewis, {Cathryn M.} and Li, {Qingqin S.} and Liu, {Chih Min} and Martin, {Nicholas G.} and McIntosh, {Andrew M.} and Medland, {Sarah E.} and Ole Mors and Merete Nordentoft and Olsen, {Catherine M.} and David Porteous and Smith, {Daniel J.} and Stahl, {Eli A.} and Stein, {Murray B.} and Danuta Wasserman and Thomas Werge and Whiteman, {David C.} and Virginia Willour and Hilary Coon and Beckham, {Jean C.} and Kimbrel, {Nathan A.} and Ruderfer, {Douglas M.}",
note = "Funding Information: This work was supported by NIMH (grants R01MH123619, R01MH123489, R01MH099134, K01MH109765, R01MH116269, and R01MH121455). This research is also based on data from the U.S. Department of Veterans Affairs Million Veteran Program (MVP) and was supported by award I01CX001729 from the Clinical Science Research and Development Service of the Veterans Health Administration Office of Research and Development. Dr. Beckham was also supported by a Senior Research Career Scientist Award (lK6BX003777) from Clinical Science Research and Development. Research reported here was supported bythe National Institute of General Medical Sciences under award T32GM007347 (Dr. Kang). This work was also supported by Brain and Behavior Research Foundation/NARSAD Young Investigator Awards to Dr. Mullins (29551), to Dr. Shabalin (28686), and to Dr. DiBlasi (28132). Work was supported by the Huntsman Mental Health Institute, the American Foundation for Suicide Prevention (Drs. Docherty, Shabalin, DiBlasi, Bakian, and Coon), and the Clark Tanner Research Foundation. This work was also supported by research funding from Janssen Research and Development to University of Utah. Data from the Utah cohort are available through the Utah Population Database, which is partially supported by the Huntsman Cancer Institute and award P30CA42014 from the National Cancer Institute. Several statistical analyses were carried out on the Mount Sinai high-performance computing cluster (http://hpc.mssm.edu), which is supported by the NIH Office of Research Infrastructure (grants S10OD018522 and S10OD026880). This work was also conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University and the Huntsman Mental Health Institute at the University of Utah School of Medicine. Publisher Copyright: {\textcopyright} 2023 American Psychiatric Association. All rights reserved.",
year = "2023",
month = oct,
day = "1",
doi = "10.1176/appi.ajp.21121266",
language = "English",
volume = "180",
pages = "723--738",
journal = "American Journal of Psychiatry",
issn = "0002-953X",
publisher = "American Psychiatric Association",
number = "10",
}
