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 language | English |
|---|---|
| Journal | American Journal of Psychiatry |
| Volume | 180 |
| Issue number | 10 |
| Pages (from-to) | 723-738 |
| Number of pages | 16 |
| ISSN | 0002-953X |
| DOIs | |
| Publication status | Published - 2023 |
Bibliographical note
Publisher Copyright:© 2023 American Psychiatric Association. All rights reserved.
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In: American Journal of Psychiatry, Vol. 180, No. 10, 2023, p. 723-738.
Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - GWAS Meta-Analysis of Suicide Attempt
T2 - Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors
AU - Docherty, Anna R.
AU - Mullins, Niamh
AU - Ashley-Koch, Allison E.
AU - Qin, Xuejun
AU - Coleman, Jonathan R.I.
AU - Shabalin, Andrey
AU - Kang, Joo Eun
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AU - Wendt, Frank
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AU - Campos, Adrian I.
AU - DiBlasi, Emily
AU - Fullerton, Janice M.
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AU - Bakian, Amanda V.
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AU - Rentería, Miguel E.
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AU - Trafton, Jodie
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AU - Christensen, Erik D.M.D.
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AU - Edwards, Alexis C.
AU - Fernández-Aranda, Fernando
AU - Galfalvy, Hanga
AU - Gandal, Michael
AU - Gorwood, Philip
AU - Guo, Yiran
AU - Hafferty, Jonathan D.
AU - Hakonarson, Hakon
AU - Halmi, Katherine A.
AU - Hishimoto, Akitoyo
AU - Jain, Sonia
AU - Jamain, Stéphane
AU - Jiménez-Murcia, Susana
AU - Johnson, Craig
AU - Kaplan, Allan S.
AU - Kaye, Walter H.
AU - Keel, Pamela K.
AU - Kennedy, James L.
AU - Kim, Minsoo
AU - Klump, Kelly L.
AU - Levey, Daniel F.
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AU - Liao, Shih Cheng
AU - Lieb, Klaus
AU - Lilenfeld, Lisa
AU - Marshall, Christian R.
AU - Mitchell, James E.
AU - Okazaki, Satoshi
AU - Otsuka, Ikuo
AU - Pinto, Dalila
AU - Powers, Abigail
AU - Ramoz, Nicolas
AU - Ripke, Stephan
AU - Roepke, Stefan
AU - Rozanov, Vsevolod
AU - Scherer, Stephen W.
AU - Schmahl, Christian
AU - Sokolowski, Marcus
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AU - Su, Mei Hsin
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AU - Ware, Erin B.
AU - Watson, Hunna J.
AU - Witt, Stephanie H.
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AU - Van Der Auwera, Sandra
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AU - Bigdeli, Tim B.
AU - Binder, Elisabeth B.
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AU - Boks, Marco P.
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AU - Castelao, Enrique
AU - Cervilla, Jorge A.
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AU - Corvin, Aiden
AU - Craddock, Nicholas
AU - Djurovic, Srdjan
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AU - Forstner, Andreas J.
AU - Frye, Mark
AU - Gatt, Justine M.
AU - Giegling, Ina
AU - Grabe, Hans J.
AU - Green, Melissa J.
AU - Grevet, Eugenio H.
AU - Grigoroiu-Serbanescu, Maria
AU - Gutierrez, Blanca
AU - Guzman-Parra, Jose
AU - Hamshere, Marian L.
AU - Hartmann, Annette M.
AU - Hauser, Joanna
AU - Heilmann-Heimbach, Stefanie
AU - Hoffmann, Per
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AU - Kahn, René S.
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AU - Kendler, Kenneth S.
AU - Kloiber, Stefan
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AU - Kogevinas, Manolis
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AU - Mehta, Divya
AU - Melle, Ingrid
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AU - Nievergelt, Caroline
AU - Nöthen, Markus M.
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AU - Pato, Carlos
AU - Pato, Michele T.
AU - Penninx, Brenda W.J.H.
AU - Potash, James B.
AU - Power, Robert A.
AU - Preisig, Martin
AU - Quested, Digby
AU - Ramos-Quiroga, Josep Antoni
AU - Reif, Andreas
AU - Ribasés, Marta
AU - Richarte, Vanesa
AU - Rietschel, Marcella
AU - Rivera, Margarita
AU - Roberts, Andrea
AU - Roberts, Gloria
AU - Rouleau, Guy A.
AU - Rovaris, Diego L.
AU - Sanders, Alan R.
AU - Schofield, Peter R.
AU - Schulze, Thomas G.
AU - Scott, Laura J.
AU - Serretti, Alessandro
AU - Shi, Jianxin
AU - Sirignano, Lea
AU - Sklar, Pamela
AU - Smeland, Olav B.
AU - Smoller, Jordan W.
AU - Sonuga-Barke, Edmund J.S.
AU - Trzaskowski, MacIej
AU - Tsuang, Ming T.
AU - Turecki, Gustavo
AU - Vilar-Ribó, Laura
AU - Vincent, John B.
AU - Völzke, Henry
AU - Walters, James T.R.
AU - Weickert, Cynthia Shannon
AU - Weickert, Thomas W.
AU - Weissman, Myrna M.
AU - Williams, Leanne M.
AU - Wray, Naomi R.
AU - Zai, Clement C.
AU - Agerbo, Esben
AU - Børglum, Anders D.
AU - Breen, Gerome
AU - Demontis, Ditte
AU - Erlangsen, Annette
AU - Gelernter, Joel
AU - Glatt, Stephen J.
AU - Hougaard, David M.
AU - Hwu, Hai Gwo
AU - Kuo, Po Hsiu
AU - Lewis, Cathryn M.
AU - Li, Qingqin S.
AU - Liu, Chih Min
AU - Martin, Nicholas G.
AU - McIntosh, Andrew M.
AU - Medland, Sarah E.
AU - Mors, Ole
AU - Nordentoft, Merete
AU - Olsen, Catherine M.
AU - Porteous, David
AU - Smith, Daniel J.
AU - Stahl, Eli A.
AU - Stein, Murray B.
AU - Wasserman, Danuta
AU - Werge, Thomas
AU - Whiteman, David C.
AU - Willour, Virginia
AU - Coon, Hilary
AU - Beckham, Jean C.
AU - Kimbrel, Nathan A.
AU - Ruderfer, Douglas M.
N1 - Publisher Copyright: © 2023 American Psychiatric Association. All rights reserved.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1176/appi.ajp.21121266
DO - 10.1176/appi.ajp.21121266
M3 - Journal article
C2 - 37777856
AN - SCOPUS:85176353814
SN - 0002-953X
VL - 180
SP - 723
EP - 738
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 10
ER -