TY - JOUR

T1 - GWAS Meta-Analysis of Suicide Attempt: 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, JooEun

AU - Murnyak, Balasz

AU - Wendt, Frank

AU - Adams, Mark

AU - Campos, Adrian I.

AU - DiBlasi, Emily

AU - Fullerton, Janice M.

AU - Kranzler, Henry R.

AU - Bakian, Amanda V.

AU - Monson, Eric T.

AU - Rentería, Miguel E.

AU - Walss-Bass, Consuelo

AU - Andreassen, Ole A.

AU - Behera, Chittaranjan

AU - Bulik, Cynthia M.

AU - Edenberg, Howard J.

AU - Kessler, Ronald C.

AU - Mann, J. John

AU - Nurnberger, John I.

AU - Pistis, Giorgio

AU - Streit, Fabian

AU - Ursano, Robert J.

AU - Polimanti, Renato

AU - Dennis, Michelle

AU - Garrett, Melanie

AU - Hair, Lauren

AU - Harvey, Philip

AU - Hauser, Elizabeth R.

AU - Hauser, Michael A.

AU - Huffman, Jennifer

AU - Jacobson, Daniel

AU - Madduri, Ravi

AU - McMahon, Benjamin

AU - Oslin, David W.

AU - Trafton, Jodie

AU - Awasthi, Swapnil

AU - Berrettini, Wade H.

AU - Bohus, Martin

AU - Chang, Xiao

AU - Chen, Hsi-Chung

AU - Chen, Wei J.

AU - Christensen, Erik D.

AU - Crow, Scott

AU - Duriez, Philibert

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.

AU - Li, Dong

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

AU - Starnawska, Anna

AU - Strober, Michael

AU - Su, Mei-Hsin

AU - Thornton, Laura M.

AU - Treasure, Janet

AU - Ware, Erin B.

AU - Watson, Hunna J.

AU - Witt, Stephanie H.

AU - Woodside, D. Blake

AU - Yilmaz, Zeynep

AU - Zillich, Lea

AU - Adolfsson, Rolf

AU - Agartz, Ingrid

AU - Alda, Martin

AU - Alfredsson, Lars

AU - Appadurai, Vivek

AU - Artigas, María Soler

AU - Van der Auwera, Sandra

AU - Azevedo, M. Helena

AU - Bass, Nicholas

AU - Bau, Claiton H.D.

AU - Baune, Bernhard T.

AU - Bellivier, Frank

AU - Berger, Klaus

AU - Biernacka, Joanna M.

AU - Bigdeli, Tim B.

AU - Binder, Elisabeth B.

AU - Boehnke, Michael

AU - Boks, Marco P.

AU - Braff, David L.

AU - Bryant, Richard

AU - Budde, Monika

AU - Byrne, Enda M.

AU - Cahn, Wiepke

AU - Castelao, Enrique

AU - Cervilla, Jorge A.

AU - Chaumette, Boris

AU - Corvin, Aiden

AU - Craddock, Nicholas

AU - Djurovic, Srdjan

AU - Foo, Jerome C.

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

AU - Ising, Marcus

AU - Jones, Ian

AU - Jones, Lisa A.

AU - Jonsson, Lina

AU - Kahn, René S.

AU - Kelsoe, John R.

AU - Kendler, Kenneth S.

AU - Kloiber, Stefan

AU - Koenen, Karestan C.

AU - Kogevinas, Manolis

AU - Krebs, Marie-Odile

AU - Landén, Mikael

AU - Leboyer, Marion

AU - Lee, Phil H.

AU - Levinson, Douglas F.

AU - Liao, Calwing

AU - Lissowska, Jolanta

AU - Mayoral, Fermin

AU - McElroy, Susan L.

AU - McGrath, Patrick

AU - McGuffin, Peter

AU - McQuillin, Andrew

AU - Mehta, Divya

AU - Melle, Ingrid

AU - Mitchell, Philip B.

AU - Molina, Esther

AU - Morken, Gunnar

AU - Nievergelt, Caroline

AU - Nöthen, Markus M.

AU - O’Donovan, Michael C.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

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.

PY - 2023/10/1

Y1 - 2023/10/1

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 variationof 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 establishessignificant 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 variationof 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 establishessignificant 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.

KW - Depressive Disorder, Major/genetics

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Polymorphism, Single Nucleotide/genetics

KW - Risk Factors

KW - Suicidal Ideation

KW - Suicide, Attempted

UR - https://pubmed.ncbi.nlm.nih.gov/37777856/

UR - https://www.mendeley.com/catalogue/afaba2b7-cc96-3dcb-b1e6-9b407611f15d/

U2 - 10.1176/appi.ajp.21121266

DO - 10.1176/appi.ajp.21121266

M3 - Article

C2 - 37777856

VL - 180

SP - 723

EP - 738

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

SN - 0002-953X

IS - 10

ER -