Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans
Authors: Kimbrel Nathan A. , Ashley-Koch Allison E. , Qin Xue J. , Lindquist Jennifer H. , Garrett Melanie E. , Dennis Michelle F. , Hair Lauren P. , Huffman Jennifer E. , Jacobson Daniel A. , Madduri Ravi K. , Trafton Jodie A. , Coon Hilary , Docherty Anna R. , Mullins Niamh , Ruderfer Douglas M. , Harvey Philip D. , McMahon Benjamin H. , Oslin David W. , Beckham Jean C. , Hauser Elizabeth R. , Hauser Michael A. ,   Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program, Agarwal Khushbu , Ashley-Koch Allison E. , Aslan Mihaela , Beckham Jean C. , Begoli Edmond , Bhattacharya Tanmoy , Brown Ben , Calhoun Patrick S. , Cheung Kei-Hoi , Choudhury Sutanay , Cliff Ashley M. , Cohn Judith D. , Crivelli Silvia , Cuellar-Hengartner Leticia , Deangelis Haedi E. , Dennis Michelle F. , Dhaubhadel Sayera , Finley Patrick D. , Ganguly Kumkum , Garvin Michael R. , Gelernter Joel E. , Hair Lauren P. , Harvey Phillip D. , Hauser Elizabeth R. , Hauser Michael A. , Hengartner Nick W. , Jacobson Daniel A. , Jones Piet C. , Kainer David , Kaplan Alan D. , Katz Ira R. , Kember Rachel L. , Kimbrel Nathan A. , Kirby Angela C. , Ko John C. , Kolade Beauty , Lagergren John H. , Lane Matthew J. , Levey Daniel F. , Levin Drew , Lindquist Jennifer H. , Liu Xianlian , Madduri Ravi K. , Manore Carrie , Martins Susana B. , McCarthy John F. , McDevitt-Cashman Mikaela , McMahon Benjamin H. , Miller Izaak , Morrow Destinee , Oslin David W. , Pavicic-Venegas Mirko , Pestian John , Pyarajan Saiju , Qin Xue J. , Rajeevan Nallakkandi , Ramsey Christine M. , Ribeiro Ruy , Rodriguez Alex , Romero Jonathan , Santel Daniel , Schaefferkoetter Noah , Shi Yunling , Stein Murray B. , Sullivan Kyle , Sun Ning , Tamang Suzanne R. , Townsend Alice , Trafton Jodie A. , Walker Angelica , Wang Xiange , Wangia-Anderson Victoria , Yang Renji , Yoon Hong-Jun , Yoo Shinjae , Zamora-Resendiz Rafael , Zhao Hongyu , Docherty Anna R , Mullins Niamh , 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 , 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 , 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 , 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 , Nurnberger John I , Olsen Catherine , Porteous David , Smith Daniel J , Stahl Eli A , Stein Murray B , Wasserman Danuta , Werge Thomas , Whiteman David C , Willour Virginia , Coon Hilary , Ruderfer Douglas M , Dedert Eric , Elbogen Eric B. , Fairbank John A. , Hurley Robin A. , Kilts Jason D. , Martindale Sarah L. , Marx Christine E. , McDonald Scott D. , Moore Scott D. , Morey Rajendra A. , Naylor Jennifer C. , Rowland Jared , Shura Robert D. , Swinkels Cindy , Tupler Larry A. , Van Voorhees Elizabeth E. , Yoash-Gantz Ruth , Gaziano J. Michael , Muralidhar Sumitra , Ramoni Rachel , Chang Kyong-Mi , O’Donnell Christopher J. , Tsao Philip S. , Breeling James , Hauser Elizabeth , Sun Yan , Huang Grant , Casas Juan P. , Moser Jennifer , Whitbourne Stacey B. , Brewer Jessica V. , Conner Todd , Argyres Dean P. , Stephens Brady , Brophy Mary T. , Humphries Donald E. , Selva Luis E. , Do Nhan , Shayan Shahpoor (Alex) , Cho Kelly , Churby Lori , Wilson Peter , McArdle Rachel , Dellitalia Louis , Mattocks Kristin , Harley John , Whittle Jeffrey , Jacono Frank , Wells John , Gutierrez Salvador , Gibson Gretchen , Hammer Kimberly , Kaminsky Laurence , Villareal Gerardo , Kinlay Scott , Xu Junzhe , Hamner Mark , Mathew Roy , Bhushan Sujata , Iruvanti Pran , Godschalk Michael , Ballas Zuhair , Ivins Douglas , Mastorides Stephen , Moorman Jonathan , Gappy Saib , Klein Jon , Ratcliffe Nora , Florez Hermes , Okusaga Olaoluwa , Murdoch Maureen , Sriram Peruvemba , Yeh Shing Shing , Tandon Neeraj , Jhala Darshana , Liangpunsakul Suthat , Oursler Kris Ann , Whooley Mary , Ahuja Sunil , Constans Joseph , Meyer Paul , Greco Jennifer , Rauchman Michael , Servatius Richard , Gaddy Melinda , Wallbom Agnes , Morgan Timothy , Stapley Todd , Sherman Scott , Ross George , Strollo Patrick , Boyko Edward , Meyer Laurence , Gupta Samir , Huq Mostaqul , Fayad Joseph , Hung Adriana , Lichy Jack , Hurley Robin , Robey Brooks , Striker Robert 
Published: December 2022

Importance

Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.

Objective

To identify novel, replicable genomic risk loci for SITB.

Design, Setting, and Participants

This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.

Main Outcome and Measures

SITB.

Results

A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P &amp;lt; 5 × 10−8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r &amp;gt; 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.

Conclusions and Relevance

The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.