Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans

Media type: E-Article
Title: Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans
Contributor: 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.; Agarwal, Khushbu; Ashley-Koch, Allison E.; Aslan, Mihaela; [...]
imprint: American Medical Association (AMA), 2023
Published in: JAMA Psychiatry
Language: English
DOI: 10.1001/jamapsychiatry.2022.3896
ISSN: 2168-622X
Origination:
Footnote:
Description: <jats:sec><jats:title>Importance</jats:title><jats:p>Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To identify novel, replicable genomic risk loci for SITB.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and Participants</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Main Outcome and Measures</jats:title><jats:p>SITB.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (<jats:italic>P</jats:italic> &amp;lt; 5 × 10<jats:sup>−8</jats:sup>) 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 <jats:italic>ESR1,</jats:italic> rs12808482 in <jats:italic>DRD2,</jats:italic> rs77641763 in <jats:italic>EXD3</jats:italic>, rs10671545 in <jats:italic>DCC</jats:italic>, and rs36006172 in <jats:italic>TRAF3.</jats:italic> Associations for <jats:italic>FBXL19</jats:italic> and <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/nuccore/14280281"><jats:italic>AC018880</jats:italic></jats:ext-link><jats:italic>.2</jats:italic> were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including <jats:italic>FURIN, TSNARE1,</jats:italic> and the <jats:italic>NCAM1-TTC12-ANKK1-DRD2</jats:italic> 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 (<jats:italic>POM121L2</jats:italic> and <jats:italic>METTL15</jats:italic>/<jats:italic>LINC02758</jats:italic>) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (<jats:italic>PET112/GATB</jats:italic>) 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 (<jats:italic>r</jats:italic> &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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for <jats:italic>ESR1</jats:italic>, <jats:italic>DRD2</jats:italic>, <jats:italic>TRAF3</jats:italic>, and <jats:italic>DCC</jats:italic> 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.</jats:p></jats:sec>

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