Genome-wide association study meta-analysis of suicide attempt identifies twelve genome-wide significant loci and implicates genetic risks for specific health factors

Doherty, Anna, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379, Hamshere, Marian ORCID: https://orcid.org/0000-0002-8990-0958, Jones, Ian ORCID: https://orcid.org/0000-0001-5821-5889, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862 and Walters, James ORCID: https://orcid.org/0000-0002-6980-4053 2023. Genome-wide association study meta-analysis of suicide attempt identifies twelve genome-wide significant loci and implicates genetic risks for specific health factors. The American Journal of Psychiatry 180 (10) , pp. 723-738. 10.1176/appi.ajp.21121266

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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 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. 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. Suicide accounted for more than 700,000 deaths worldwide in 2019 and was the fourth leading cause of death among 15- to 29-year-olds (1). Suicide attempt is even more common (2–4). Suicide attempt is strongly associated with psychiatric conditions, poor quality of life, traumatic experiences, and social and economic burden (1) and is the single strongest predictor of future suicide death (5). Heritability estimates for suicidal thoughts and behaviors from twin and family studies range from 30% to 55% (6), and recent large-scale genome-wide association studies (GWASs) have yielded promising and replicable results. The International Suicide Genetics Consortium (ISGC) (total N=549,743; 29,782 cases) identified two loci reaching genome-wide significance for suicide attempt in individuals of primarily European ancestry admixtures, on chromosomes 6 (index SNP: rs71557378; p=1.97×10−8) and 7 (index SNP: rs62474683; p=1.91×10−10) (7). The intergenic locus on chromosome 7 remained significant after conditioning on psychiatric disorders and was independently replicated (p=3.27×10−3) (8) in the Million Veteran Program (MVP) cohort (9). The MVP cohort GWAS of suicide attempt (total N=409,153; 14,089 cases) resulted in two genome-wide significant multi-ancestry loci, on chromosomes 20 (index SNP: rs56817213; p=3.64×10−9) and 1 (index SNP: rs72730526; p=3.69×10−8) (8). A top signal identified at the dopamine receptor D2 locus (p=1.77×10−7) also showed moderate association in the ISGC GWAS (p=7.97×10−4) (7). These studies established the complexity of the common variant genetic architecture of suicide attempt and demonstrated the critical role of sample size for discovering novel, replicable risk loci for suicide phenotypes through GWASs (10). Together, these GWASs suggested that larger studies will identify additional genomic risk loci and refine genetic risk metrics. The objective of the present study was to conduct a meta-analysis of the ISGC and MVP studies (total N=958,896; 43,871 suicide attempt and suicide death cases). Moreover, there is considerable need to increase the diversity and generalizability of GWAS data (11). Combining all ISGC and MVP cohorts allowed for the largest GWAS meta-analyses of European, African, and East Asian ancestry admixtures to date. We also tested for gene set enrichment and functional follow-up specific to all included ancestral admixture populations.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	Full list of authors and consortia:- Anna R. Docherty, Ph.D., Niamh Mullins, Ph.D., Allison E. Ashley-Koch, Ph.D., Xuejun Qin, Ph.D., Jonathan R.I. Coleman, Ph.D., Andrey Shabalin, Ph.D., JooEun Kang, Ph.D., Balasz Murnyak, Ph.D., Frank Wendt, Ph.D., Mark Adams, Ph.D., Adrian I. Campos, Ph.D., Emily DiBlasi, Ph.D., Janice M. Fullerton, Ph.D., Henry R. Kranzler, M.D., Amanda V. Bakian, Ph.D., Eric T. Monson, M.D., Ph.D., Miguel E. Rentería, Ph.D., Consuelo Walss-Bass, Ph.D., Ole A. Andreassen, M.D., Ph.D., Chittaranjan Behera, M.D., Cynthia M. Bulik, Ph.D., Howard J. Edenberg, Ph.D., Ronald C. Kessler, Ph.D., J. John Mann, M.D., John I. Nurnberger Jr., M.D., Ph.D., Giorgio Pistis, Ph.D., Fabian Streit, Ph.D., Robert J. Ursano, M.D., Renato Polimanti, Ph.D., Michelle Dennis, B.S., Melanie Garrett, M.S., Lauren Hair, M.S., Philip Harvey, Ph.D., Elizabeth R. Hauser, Ph.D., Michael A. Hauser, Ph.D., Jennifer Huffman, Ph.D., Daniel Jacobson, Ph.D., Ravi Madduri, M.S., Benjamin McMahon, Ph.D., David W. Oslin, M.D., Jodie Trafton, Ph.D., Swapnil Awasthi, M.Sc., Wade H. Berrettini, M.D., Ph.D., Martin Bohus, M.D., Xiao Chang, Ph.D., Hsi-Chung Chen, M.D., Ph.D., Wei J. Chen, M.D., Ph.D., Erik D. Christensen, M.D., Scott Crow, M.D., Philibert Duriez, M.D., Alexis C. Edwards, Ph.D., Fernando Fernández-Aranda, Ph.D., Hanga Galfalvy, Ph.D., Michael Gandal, Ph.D., Philip Gorwood, M.D., Ph.D., Yiran Guo, Ph.D., Jonathan D. Hafferty, M.B.Ch.B., Hakon Hakonarson, M.D., Ph.D., Katherine A. Halmi, M.D., Akitoyo Hishimoto, M.D., Ph.D., Sonia Jain, Ph.D., Stéphane Jamain, Ph.D., Susana Jiménez-Murcia, Ph.D., Craig Johnson, Ph.D., Allan S. Kaplan, M.D., F.R.C.P.(C), Walter H. Kaye, M.D., Pamela K. Keel, Ph.D., James L. Kennedy, M.D., F.R.C.P.(C), Minsoo Kim, B.S., Kelly L. Klump, Ph.D., Daniel F. Levey, Ph.D., Dong Li, Ph.D., Shih-Cheng Liao, Ph.D., Klaus Lieb, M.D., Lisa Lilenfeld, Ph.D., Christian R. Marshall, Ph.D., James E. Mitchell, M.D., Satoshi Okazaki, M.D., Ph.D., Ikuo Otsuka, M.D., Ph.D., Dalila Pinto, Ph.D., Abigail Powers, Ph.D., Nicolas Ramoz, Ph.D., Stephan Ripke, M.D., Ph.D., Stefan Roepke, M.D., Vsevolod Rozanov, M.D., Ph.D., Stephen W. Scherer, Ph.D., F.R.S.C., Christian Schmahl, M.D., Marcus Sokolowski, Ph.D., Anna Starnawska, Ph.D., Michael Strober, Ph.D., Mei-Hsin Su, Ph.D., Laura M. Thornton, Ph.D., Janet Treasure, Ph.D., F.R.C.P., Erin B. Ware, Ph.D., M.P.H., Hunna J. Watson, Ph.D., Stephanie H. Witt, Ph.D., D. Blake Woodside, M.D., Zeynep Yilmaz, Ph.D., Lea Zillich, M.Sc., Rolf Adolfsson, Ph.D., Ingrid Agartz, M.D., Ph.D., Martin Alda, M.D., Lars Alfredsson, Ph.D., Vivek Appadurai, Ph.D., María Soler Artigas, Ph.D., Sandra Van der Auwera, Ph.D., M. Helena Azevedo, Ph.D., Nicholas Bass, M.R.C.Psych., Claiton H.D. Bau, Ph.D., Bernhard T. Baune, Ph.D., Frank Bellivier, Ph.D., Klaus Berger, M.D., Joanna M. Biernacka, Ph.D., Tim B. Bigdeli, Ph.D., Elisabeth B. Binder, M.D., Ph.D., Michael Boehnke, Ph.D., Marco P. Boks, Ph.D., David L. Braff, M.D., Richard Bryant, Ph.D., Monika Budde, Dipl.-Psych., Enda M. Byrne, Ph.D., Wiepke Cahn, Ph.D., Enrique Castelao, M.Sc., Jorge A. Cervilla, M.D., Ph.D., Boris Chaumette, M.D., Ph.D., Aiden Corvin, Ph.D., Nicholas Craddock, Ph.D., Srdjan Djurovic, Ph.D., Jerome C. Foo, Ph.D., Andreas J. Forstner, M.D., Mark Frye, M.D., Justine M. Gatt, Ph.D., Ina Giegling, Ph.D., Hans J. Grabe, M.D., Melissa J. Green, Ph.D., Eugenio H. Grevet, Ph.D., Maria Grigoroiu-Serbanescu, Ph.D., Blanca Gutierrez, Ph.D., Jose Guzman-Parra, Ph.D., Marian L. Hamshere, Ph.D., Annette M. Hartmann, Ph.D., Joanna Hauser, Ph.D., Stefanie Heilmann-Heimbach, Ph.D., Per Hoffmann, Ph.D., Marcus Ising, Ph.D., Ian Jones, Ph.D., Lisa A. Jones, Ph.D., Lina Jonsson, Ph.D., René S. Kahn, M.D., Ph.D., John R. Kelsoe, M.D., Kenneth S. Kendler, M.D., Stefan Kloiber, M.D., Karestan C. Koenen, Ph.D., Manolis Kogevinas, Ph.D., Marie-Odile Krebs, M.D., Ph.D., Mikael Landén, M.D., Ph.D., Marion Leboyer, Ph.D., Phil H. Lee, Ph.D., Douglas F. Levinson, M.D., Calwing Liao, Ph.D., Jolanta Lissowska, Ph.D., Fermin Mayoral, Ph.D., Susan L. McElroy, M.D., Patrick McGrath, M.D., Peter McGuffin, Ph.D., Andrew McQuillin, Ph.D., Divya Mehta, Ph.D., Ingrid Melle, M.D., Ph.D., Philip B. Mitchell, M.D., Esther Molina, Ph.D., Gunnar Morken, Ph.D., Caroline Nievergelt, Ph.D., Markus M. Nöthen, M.D., Michael C. O’Donovan, F.R.C.Psych., Ph.D., Roel A. Ophoff, Ph.D., Michael J. Owen, F.R.C.Psych., Ph.D., Carlos Pato, M.D., Ph.D., Michele T. Pato, M.D., Brenda W.J.H. Penninx, Ph.D., James B. Potash, M.D., Robert A. Power, Ph.D., Martin Preisig, M.D., Digby Quested, M.D., Josep Antoni Ramos-Quiroga, M.D., Ph.D., Andreas Reif, M.D., Marta Ribasés, Ph.D., Vanesa Richarte, M.D., Ph.D., Marcella Rietschel, M.D., Margarita Rivera, Ph.D., Andrea Roberts, M.P.H., Ph.D., Gloria Roberts, Ph.D., Guy A. Rouleau, Ph.D., Diego L. Rovaris, Ph.D., Alan R. Sanders, M.D., Peter R. Schofield, Ph.D., D.Sc., Thomas G. Schulze, M.D., Laura J. Scott, Ph.D., Alessandro Serretti, M.D., Jianxin Shi, Ph.D., Lea Sirignano, M.Sc., Pamela Sklar, Ph.D., Olav B. Smeland, M.D., Ph.D., Jordan W. Smoller, M.D., Sc.D., Edmund J.S. Sonuga-Barke, Ph.D., Maciej Trzaskowski, Ph.D., Ming T. Tsuang, Ph.D., Gustavo Turecki, Ph.D., Laura Vilar-Ribó, B.Sc., John B. Vincent, Ph.D., Henry Völzke, M.D., James T.R. Walters, Ph.D., Cynthia Shannon Weickert, Ph.D., Thomas W. Weickert, Ph.D., Myrna M. Weissman, Ph.D., Leanne M. Williams, Ph.D., Naomi R. Wray, Ph.D., Clement C. Zai, Ph.D., Esben Agerbo, Dr.Med.Sc., Anders D. Børglum, Ph.D., Gerome Breen, Ph.D., Ditte Demontis, Ph.D., Annette Erlangsen, Ph.D., Joel Gelernter, M.D., Stephen J. Glatt, Ph.D., David M. Hougaard, M.D., Hai-Gwo Hwu, M.D., Po-Hsiu Kuo, Ph.D., Cathryn M. Lewis, Ph.D., Qingqin S. Li, Ph.D., Chih-Min Liu, M.D., Nicholas G. Martin, Ph.D., Andrew M. McIntosh, M.D., Sarah E. Medland, Ph.D., Ole Mors, Ph.D., Merete Nordentoft, M.D., Catherine M. Olsen, Ph.D., David Porteous, Ph.D., Daniel J. Smith, M.D., F.R.C.Psych., Eli A. Stahl, Ph.D., Murray B. Stein, M.D., M.P.H., Danuta Wasserman, M.D., Ph.D., Thomas Werge, Ph.D., David C. Whiteman, M.B.B.S., Ph.D., Virginia Willour, Ph.D., VA Million Veteran Program (MVP), MVP Suicide Exemplar Workgroup, Suicide Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Eating Disorder Working Group of the Psychiatric Genomics Consortium, German Borderline Genomics Consortium, Hilary Coon, Ph.D., Jean C. Beckham, Ph.D., Nathan A. Kimbrel, Ph.D., Douglas M. Ruderfer, Ph.D.
Publisher:	Psychiatry Online
ISSN:	0002-953X
Date of First Compliant Deposit:	5 June 2023
Date of Acceptance:	4 May 2023
Last Modified:	17 Nov 2023 00:46
URI:	https://orca.cardiff.ac.uk/id/eprint/160171

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