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Principal Investigator: JEAN C. BECKHAM
Organization: DURHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
On average, 18 Veterans die by suicide each day. In fact, from 2009 to 2018, more than 64,000 Veterans died
by suicide, which is roughly the same number of U.S. military fatalities that resulted from the wars in Vietnam,
Iraq, and Afghanistan combined. While heritability estimates for suicidal thoughts and behaviors range from 30-
55%, the genetic basis of suicide remains largely unknown. Our research team has led and participated in
many of the largest genome-wide association studies (GWAS) of suicidal thoughts and behaviors to date,
including each of the largest conducted in Veteran and military samples. Our most recent work has involved
conducting a GWAS of suicide attempts among more than 400,000 Veterans enrolled in the Million Veteran
Program (MVP). This study identified multiple pan-ethnic and ancestry-specific genome-wide significant loci
associated with risk for attempting suicide among Veterans. Moreover, pathway analyses found evidence of
overrepresentation of many biological pathways with high clinical significance, including oxytocin signaling,
glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. In
parallel, we have been studying a broad array of environmental risk factors for suicidal thoughts and behaviors
in Veterans, such as sexual trauma, PTSD, depression, substance use disorders, borderline personality
disorder, chronic pain, traumatic brain injury, and sleep disturbance (among others). We are also actively
working to identify novel environmental risk factors, including geospatial factors [e.g., socioeconomic status
(SES), rurality], many of which have not been previously examined in large-scale genetic studies of suicide
risk. We believe that complete understanding of a complex phenotype requires understanding of relevant
genetic risk factors, relevant environmental risk factors, as well as the ways in which these risk factors interact.
Accordingly, during the next phase of our program of research, we propose to conduct the largest gene-by-
environment genome-wide interaction study (GEWIS) of suicidal thoughts and behaviors to date. This work will
enable us to identify new ways to improve the identification of high-risk Veterans, while also greatly increasing
our understanding of the biological basis of suicide. Our long-term goal is to develop effective screening and
intervention strategies to reduce the occurrence of suicide and suicidal behavior among Veterans. The overall
objective of this specific application is to discover novel, replicable GxE interactions that increase Veterans’
risk for suicidal thoughts and behaviors. The rationale for this research is that identification of genetic variants,
environmental factors, and GxE interactions that are reliably associated with suicidal thoughts and behaviors
could lead to improved identification of high-risk Veterans and the discovery of additional clinically-meaningful
biological pathways. Such findings could, in turn, lead to new and improved treatment and prevention
approaches. In Aim 1, we will determine the environmental risk factors most strongly associated with the
occurrence of suicide attempts, suicidal ideation, and suicide deaths within the MVP cohort. In Aim 2, we will
conduct the largest GEWIS of suicidal thoughts and behaviors to date to identify novel, replicable GxE
interactions predictive of suicide attempts, suicidal ideation, and suicide deaths among Veterans. In Aim 3, in
order to evaluate the clinical utility of our findings, we will work with our operational partners to determine if the
addition of our top genetic risk factors, environmental risk factors, and GxE interactions improves the predictive
utility of the Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET)
suicide risk algorithm within the MVP cohort. Findings obtained from the proposed work could fundamentally
shift understanding of the biology of suicide, lead to new and improved treatments, and improve VA’s efforts to
identify and intervene with Veterans at risk for suicide. As such, the present application has tremendous
potential to advanced VA’s mission and improve Veterans’ health, safety, and well-being.
Terms: <Address><Aeroseb-HC><Afghanistan><Algorithms><Approaches to prevention><Armed Forces Personnel><Biological><Biology><Borderline Personality Disorder><Brain Trauma><Cell Communication and Signaling><Cell Signaling><Cetacort><Circadian Rhythms><Clinical><Complex><Cort-Dome><Cortef><Cortenema><Cortisol><Cortispray><Cortril><Data><Dermacort><Eldecort><Enrollment><Environment><Environmental Factor><Environmental Risk Factor><Ethnic Origin><Ethnicity><Feeling suicidal><GWA study><GWAS><Gene variant><Gene x Environment Interaction><Genes><Genetic><Genetic Markers><Genetic Risk><Genetic predisposing factor><Genetic study><Glutamates><Goals><GxE interaction><Health><Heritability><Human Genetics><Hydrocortisone><Hydrocortone><Hytone><International><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Iraq><L-Glutamate><Lead><Mental Depression><Mental disorders><Mental health disorders><Military><Military Personnel><Mission><Network Analysis><Nutracort><Nyctohemeral Rhythm><Ocytocin><Oxytocin><PTSD><Pathway Analysis><Pathway interactions><Pb element><Personal Satisfaction><Phase><Phenotype><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Prevention approach><Probabilistic Models><Probability Models><Proctocort><Psychiatric Disease><Psychiatric Disorder><Qualifying><Recombinant Oxytocin><Recovery><Research><Research Personnel><Researchers><Risk><Risk Factors><Risk-associated variant><Safety><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Sleep disturbances><Socio-economic status><Socioeconomic Status><Statistical Models><Substance Use Disorder><Suicidal thoughts><Suicide><Suicide attempt><Suicide precaution><Suicide prevention><Synapses><Synaptic><Traumatic Brain Injury><Twenty-Four Hour Rhythm><Veterans><Viet Nam><Vietnam><War><Work><aberrant sleep><allele variant><allelic variant><biologic><biological signal transduction><chronic pain><circadian process><clinical significance><clinically significant><cohort><daily biorhythm><depression><disrupted sleep><disturbed sleep><enroll><environment effect on gene><environmental risk><fatal attempt><fatal suicide><gene biomarker><gene environment interaction><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><genetic risk factor><genetic variant><genome scale><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide><genomewide><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><glutamatergic><heavy metal Pb><heavy metal lead><high risk><impaired sleep><improved><inherited factor><intent to die><interventional strategy><irregular sleep><member><mental illness><military population><non fatal attempt><nonfatal attempt><novel><pathway><post-trauma stress disorder><posttrauma stress disorder><prevent suicidality><prevent suicide><programs><psychiatric illness><psychological disorder><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><rurality><screening><screenings><sexual trauma><sleep disruption><sleep dysregulation><socio-economic position><socioeconomic position><statistical linear mixed models><statistical linear models><substance use and disorder><suicidal attempt><suicidal behavior><suicidal ideation><suicidal morbidity><suicidal risk><suicidal thinking><suicidality prevention><suicide behavior><suicide death><suicide ideation><suicide intervention><suicide morbidity><suicide risk><suicides><synapse><thoughts about suicide><traumatic brain damage><traumatic neurosis><well-being><wellbeing><whole genome association analysis><whole genome association studies><whole genome association study>