Genome-wide association study meta-analysis of suicide attempt identifies twelve genome-wide significant loci and implicates genetic risks for specific health factors
Authors: Docherty Anna R , Mullins Niamh , Ashley-Koch Allison E , Qin Xuejun , Coleman Jonathan R I , Shabalin Andrey , Kang JooEun , Murnyak Balasz , Wendt Frank , Adams Mark , Campos Adrian I , DiBlasi Emily , Fullerton Janice M , Kranzler Henry R , Bakian Amanda , Monson Eric T , Rentería Miguel E , Walss-Bass Consuelo , Andreassen Ole A , Bulik Cynthia M , Edenberg Howard J , Kessler Ronald C , Mann J John , Nurnberger John I , Pistis Giorgio , Streit Fabian , Ursano Robert J , Polimonti Renato , Dennis Michelle , Garrett Melanie , Hair Lauren , Harvey Philip , Hauser Elizabeth R , Hauser Michael A , Huffman Jennifer , Jacobson Daniel , Lindquist Jennifer H , Madduri Ravi , McMahon Benjamin , Oslin David W , Trafton Jodie , Awasthi Swapnil , Bergen Andrew W , Berrettini Wade H , Bohus Martin , Brandt Harry , Chang Xiao , Chen Hsi-Chung , Chen Wei J , Christensen Erik D , Crawford Steven , Crow Scott , Duriez Philibert , Edwards Alexis C , Fernández-Aranda Fernando , Fichter Manfred M , Galfalvy Hanga , Gallinger Steven , Gandal Michael , Gorwood Philip , Guo Yiran , Hafferty Jonathan D , Hakonarson Hakon , Halmi Katherine A , Hishimoto Akitoyo , Jain Sonia , Jamain Stéphane , Jiménez-Murcia Susana , Johnson Craig , Kaplan Allan S , Kaye Walter H , Keel Pamela K , Kennedy James L , Kim Minsoo , Klump Kelly L , Levey Daniel F , Li Dong , Liao Shih-Cheng , Lieb Klaus , Lilenfeld Lisa , Lori Adriana , Magistretti Pierre J , Marshall Christian R , Mitchell James E , Myers Richard M , Okazaki Satoshi , Otsuka Ikuo , Pinto Dalila , Powers Abigail , Ramoz Nicolas , Ripke Stephan , Roepke Stefan , Rozanov Vsevolod , Scherer Stephen W , Schmahl Christian , Sokolowski Marcus , Starnawska Anna , Strober Michael , Su Mei-Hsin , Thornton Laura M , Treasure Janet , Ware Erin B , Watson Hunna J , Witt Stephanie H , Woodside D Blake , Yilmaz Zeynep , Zillich Lea , Adolfsson Rolf , Agartz Ingrid , Air Tracy M , Alda Martin , Alfredsson Lars , Anjorin Adebayo , Appadurai Vivek , Artigas María Soler , Van der Auwera Sandra , Azevedo M Helena , Bass Nicholas , Bau Claiton HD , Baune Bernhard T , Bellivier Frank , Berger Klaus , Biernacka Joanna M , Bigdeli Tim B , Binder Elisabeth B , Boehnke Michael , Boks Marco P , Bosch Rosa , Braff David L , Bryant Richard , Budde Monika , Byrne Enda M , Cahn Wiepke , Casas Miguel , Castelao Enrique , Cervilla Jorge A , Chaumette Boris , Cichon Sven , Corvin Aiden , Craddock Nicholas , Craig David , Degenhardt Franziska , Djurovic Srdjan , Fanous Ayman H , Foo Jerome C , Forstner Andreas J , Frye Mark , Gatt Justine M , Gejman Pablo V , Giegling Ina , Grabe Hans J , Green Melissa J , Grevet Eugenio H , Grigoroiu-Serbanescu Maria , Gutierrez Blanca , Guzman-Parra Jose , Hamilton Steven P , Hamshere Marian L , Hartmann Annette M , Hauser Joanna , Heilmann-Heimbach Stefanie , Hoffmann Per , Ising Marcus , Jones Ian , Jones Lisa A , Jonsson Lina , Kahn René S , Kelsoe John R , Kendler Kenneth S , Kloiber Stefan , Koenen Karestan C , Kogevinas Manolis , Konte Bettina , Krebs Marie-Odile , Landén Mikael , Lawrence Jacob , Leboyer Marion , Lee Phil H , Levinson Douglas F , Liao Calwing , Lissowska Jolanta , Lucae Susanne , Mayoral Fermin , McElroy Susan L , McGrath Patrick , McGuffin Peter , McQuillin Andrew , Mehta Divya , Melle Ingrid , Milaneschi Yuri , Mitchell Philip B , Molina Esther , Morken Gunnar , Mortensen Preben Bo , Müller-Myhsok Bertram , Nievergelt Caroline , Nimgaonkar Vishwajit , Nöthen Markus M , O’Donovan Michael C , Ophoff Roel A , Owen Michael J , Pato Carlos , Pato Michele T , Penninx Brenda WJH , Pimm Jonathan , Potash James B , Power Robert A , Preisig Martin , Quested Digby , Ramos-Quiroga Josep Antoni , Reif Andreas , Ribasés Marta , Richarte Vanesa , Rietschel Marcella , Rivera Margarita , Roberts Andrea , Roberts Gloria , Rouleau Guy A , Rovaris Diego L , Rujescu Dan , Sánchez-Mora Cristina , Sanders Alan R , Schofield Peter R , Schulze Thomas G , Scott Laura J , Serretti Alessandro , Shi Jianxin , Shyn Stanley I , Sirignano Lea , Sklar Pamela , Smeland Olav B , Smoller Jordan W , Sonuga-Barke Edmund J S , Spalletta Gianfranco , Strauss John S , Świątkowska Beata , Trzaskowski Maciej , Tsuang Ming T , Turecki Gustavo , Vilar-Ribó Laura , Vincent John B , Völzke Henry , Walters James TR , Weickert Cynthia Shannon , Weickert Thomas W , Weissman Myrna M , Williams Leanne M , Wray Naomi R , Zai Clement C , Agerbo Esben , Børglum Anders D , Breen Gerome , Demontis Ditte , Erlangsen Annette , Esko Tõnu , Gelernter Joel , Glatt Stephen J , Hougaard David M , Hwu Hai-Gwo , Kuo Po-Hsiu , Lewis Cathryn M , Li Qingqin S , Liu Chih-Min , Martin Nicholas G , McIntosh Andrew M , Medland Sarah E , Mors Ole , Nordentoft Merete , Olsen Catherine M , Porteous David , Smith Daniel J , Stahl Eli A , Stein Murray B , Wasserman Danuta , Werge Thomas , Whiteman David C , Willour Virginia ,   the VA Million Veteran Program (MVP),   the 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, Coon Hilary , Beckham Jean C , Kimbrel Nathan A , Ruderfer Douglas M 
Published: July 2022

Objective

Suicidal behavior is heritable and a major cause of death worldwide. Two large-scale genome-wide association studies (GWAS) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The current 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 was comprised of 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 eQTL 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<5×10−8. These loci were mostly intergenic and implicatedDRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, andCACNG2. 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 was observed. There was shared genetic variation of SA with ADHD, smoking, and risk tolerance after conditioning SA on both major depressive disorder and post-traumatic 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 major ancestry admixtures, in veteran and civilian populations, and in attempt versus death.