GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present 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 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 variation of 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 establishes significant 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.

Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.

Introduction: The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods: To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results: Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans. Discussion: Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.

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

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 < 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 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.

Experiential avoidance is associated with medical and mental health diagnoses in a national sample of deployed Gulf War veterans.

A substantial minority of deployed Gulf War veterans developed posttraumatic stress disorder (PTSD), depression, and several chronic illnesses. Although military combat and exposure to certain nuclear, biological, and chemical agents (NBCs) increase risk for post-deployment health problems, they do not fully explain many Gulf War veteran health diagnoses and are not viable treatment targets. Experiential avoidance (EA; one's unwillingness to remain in contact with unpleasant internal experiences) is a modifiable psychosocial risk factor associated with PTSD and depression in veterans as well as pain and gastrointestinal diseases in the general population. In this study, we recruited a national sample of deployed Gulf War veterans (N = 454) to test the hypothesis that greater EA would be significantly associated with higher lifetime odds of PTSD, depression, "Gulf War Illness" (GWI/CMI), and other chronic illnesses common in this veteran cohort. Participants completed a self-report battery assessing demographic, military-related, and health-related information. Multivariate analyses showed that after adjusting for age, sex, race, combat exposure, and NBC exposure, worse EA was associated with higher lifetime odds of PTSD, depression GWI/CMI, gastrointestinal problems, irritable bowel syndrome, arthritis, fibromyalgia, and chronic fatigue syndrome (ORs ranged 1.25 to 2.89; effect sizes ranged small to large), but not asthma or chronic obstructive pulmonary disease. Our findings suggest medical and mental health providers alike should assess for EA and potentially target EA as part of a comprehensive, biopsychosocial approach to improving Gulf War veterans' health and wellbeing. Study limitations and future research directions are also discussed.

Racial and Sociodemographic Disparities in Internet Access and eHealth Intervention Utilization Among Veteran Smokers.

INTRODUCTION: Access to the internet at home may be an important barrier to electronic health (eHealth) smoking cessation interventions. The current study explored possible sociodemographic disparities in access to the internet at home among veteran smokers. METHODS: Data from participants proactively recruited and enrolled in a randomized smoking cessation effectiveness trial (N = 408) that compared a web-based smoking cessation intervention to Veterans Affairs (VA) usual care were used to examine the demographic attributes of smokers with and without internet access at home. Multivariable logistic regression was used to examine associations between demographic factors and home internet access. Data from patients randomized to the internet arm of the study (N = 205) were used to ascertain correlates of utilization of the intervention website. RESULTS: While the majority of the sample (82 %) endorsed access to the internet at home, veterans who were African-American, older, and not married were significantly less likely to have home internet access. Veterans who were African-American, older, less educated, had longer travel times to the nearest VA facility, and increased nicotine dependence were less likely to access the internet on a daily basis. While several sociodemographic variables (e.g., age, race, education, employment) were related to utilization of a free membership to a commercial, web-based smoking cessation intervention in bivariate analyses, only access to the internet at home was related to use of the smoking cessation site in adjusted results. CONCLUSION: These results highlight gaps in internet access and use among veterans and additionally underscore the importance of improving accessibility of eHealth interventions for low-income, minority, and socially disadvantaged veteran populations.

Abstinence Reinforcement Therapy (ART) for rural veterans: Methodology for an mHealth smoking cessation intervention.

INTRODUCTION: Smoking is the most preventable cause of morbidity and mortality in U.S. veterans. Rural veterans in particular have elevated risk for smoking and smoking-related illness. However, these veterans underutilize smoking cessation treatment, which suggests that interventions for rural veterans should optimize efficacy and reach. OBJECTIVE: The primary goal of the current study is to evaluate the effectiveness of an intervention that combines evidenced based treatment for smoking cessation with smart-phone based, portable contingency management on smoking rates compared to a contact control intervention in a randomized controlled trial among rural Veteran smokers. Specifically, Veterans will be randomized to receive Abstinence Reinforcement Therapy (ART) which combines evidenced based cognitive-behavioral telephone counseling (TC), a tele-medicine clinic for access to nicotine replacement (NRT), and mobile contingency management (mCM) or a control condition (i.e., TC and NRT alone) that will provide controls for therapist, medication, time and attention effects. METHODS: Smokers were identified using VHA electronic medical records and recruited proactively via telephone. Participants (N=310) are randomized to either ART or a best practice control consisting of telephone counseling and telemedicine. Participating patients will be surveyed at 3-months, 6-months and 12-months post-randomization. The primary outcome measure is self-reported and biochemically validated prolonged abstinence at 6-month follow-up. DISCUSSION: This trial is designed to test the relative effectiveness of ART compared to a telehealth-only comparison group. Dissemination of this mHealth intervention for veterans in a variety of settings would be warranted if ART improves smoking outcomes for rural veterans and is cost-effective.

Comparative Effectiveness of an Internet-Based Smoking Cessation Intervention Versus Clinic-Based Specialty Care for Veterans.

INTRODUCTION: The primary objective of this project was to examine the effectiveness of an Internet-based smoking cessation intervention combined with a tele-health medication clinic for nicotine replacement therapy (NRT) compared to referral to clinic-based smoking cessation care. METHODS: A total of 413 patients were proactively recruited from the Durham VA Medical Center and followed for 12 months. Patients were randomized to receive either a referral to VA specialty smoking cessation care (control) or to the Internet intervention and tele-health medication clinic. Primary outcomes included (1) intervention reach, (2) self-reported 7-day point prevalence abstinence rates at 3 months and 12 months, and 3) relative cost-effectiveness. RESULTS: Reach of the Internet intervention and use of smoking cessation aids were significantly greater compared to the control. At 3 months-post randomization, however, there were no significant differences in quit rates: 17% (95% CI: 12%­23%) in the Internet-based intervention compared to 12% (95% CI: 8%­17%) in the control arm. Similarly, there were no differences in quit rates at 12 months (13% vs. 16%). While costs associated with the Internet arm were higher due to increased penetration and intensity of NRT use, there were no statistically significant differences in the relative cost effectiveness (e.g., life years gained, quality adjusted life years) between the two arms. CONCLUSIONS: Current results suggest that using an electronic medical record to identify smokers and proactively offering smoking cessation services that are consistent with US Public Health Guidelines can significantly reduce smoking in veterans. Novel interventions that increase the reach of intensive treatment are needed to maximize quit rates in this population.

Multicomponent smoking cessation treatment including mobile contingency management in homeless veterans.

INTRODUCTION: Smoking rates are 80% among persons who are homeless, and these smokers have decreased odds of quitting smoking. Little is known about relapse rates among homeless smokers. More information is needed regarding both quit rates and innovative methods to treat smoking cessation among homeless smokers. Web-based contingency management (CM) approaches have been found helpful in reducing smoking among other difficult-to-treat smoker populations but have been generally limited by the need for computers or frequent clinic-based carbon monoxide (CO) monitoring. This open pilot study builds on a web-based CM approach by evaluating a smartphone-based application for CM named mobile CM (mCM). The study was conducted from January 1, 2013-April 15, 2014. METHOD: Following a 1-week training period, 20 homeless veteran smokers (≥ 10 cigarettes daily for 1 year or more and a CO baseline level ≥ 10 ppm) participated in a multicomponent smoking cessation intervention including 4 weeks of mCM. All smokers received 4 smoking cessation counseling sessions, nicotine replacement, and bupropion (if medically eligible). Participants could earn up to $815 ($480 for mCM, $100 for CO readings showing abstinence [ie, 6 ppm or less] at posttreatment and follow-up, and $35 for equipment return). RESULTS: Mean compensation for the mCM component was $286 of a possible $480. Video transmission compliance was high during the 1-week training (97%) and the 4-week treatment period (87%). Bioverified 7-day point prevalence abstinence was 50% at 4 weeks. Follow-up bioverified single assessment point prevalence abstinence was 55% at 3 months and 45% at 6 months. CONCLUSIONS: Results of this open pilot study suggest that mCM may be a useful adjunctive smoking cessation treatment component for reducing smoking among homeless veterans. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01789710.