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

Abstract

ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis 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 MeasuresSITB.ResultsA 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 < 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 > 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 RelevanceThe 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.

Assessment of the Genetic Characteristics of a Generation Born during a Long-Term Socioeconomic Crisis

“…Notably, rs6557168 allele C (ESR1), whose frequency turned out to be elevated in the crisis group, has been shown to correlate with heightened anxiety among military veterans and in the Danish population [55,56]. Additionally, rs6557168 is associated with suicidal thoughts and behaviors among US military veterans [80]. The results obtained in this paper were unexpected, with both studies showing a correlation of rs6557168 with anxiety and also indicating a positive correlation of anxiety with fertility [55,56].…”

High dimensional predictions of suicide risk in 4.2 million US Veterans using ensemble transfer learning

“…This provides a path forward to reaching deeper into the risk pool and identifying patient subgroups who may be well-suited to particular interventions, as suggested by Pisani et al 3 and Sorter et al 53 . Finally, we have provided a rich baseline model from which we can evaluate the utility of novel predictors of suicide and suicidal behavior, such as genetic markers 54 or thought markers, described in Pestian et al 55 .…”

Biological Factors Underpinning Suicidal Behaviour: An Update

“…The meta-analysis has identified cross-ancestry risk loci in the following candidate genes: Estrogen Receptor 1 ( ESR1 ), Dopamine Receptor D2 ( DRD2 ), TNF Receptor Associated Factor 3 ( TRAF3 ) and DCC Netrin 1 Receptor ( DCC ). This will further help in clarifying the molecular basis of STBs, but replication studies are needed to confirm their role in suicidality [ 36 ]. In addition, an association between SB and glucose regulation, and SB and protein localization regulation was confirmed by GWAS studies [ 37 ].…”