A Gene-by-Environment Genome-Wide Interaction Study (GEWIS) of Suicidal Thoughts and Behaviors in Veterans

退伍军人自杀想法和行为的基因与环境全基因组相互作用研究 (GEWIS)

• 批准号: 10487767
• 负责人: JEAN C. BECKHAM
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487767
• 关键词: Address; Afghanistan; Algorithms; Biological; Biology; Borderline Personality Disorder; Circadian Rhythms; Clinical; Complex; Data; Enrollment; Environment; Environmental Risk Factor; Ethnic Origin; Feeling suicidal; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic study; Glutamates; Goals; Health; Heritability; Human Genetics; Hydrocortisone; International; Intervention; Iraq; Lead; Mental Depression; Mental disorders; Military Personnel; Mission; Oxytocin; Pathway Analysis; Pathway interactions; Personal Satisfaction; Phase; Phenotype; Post-Traumatic Stress Disorders; Prevention approach; Qualifying; Recovery; Research; Research Personnel; Risk; Risk Factors; Safety; Sampling; Signal Transduction; Sleep disturbances; Socioeconomic Status; Statistical Models; Substance Use Disorder; Suicide; Suicide attempt; Suicide prevention; Synapses; Traumatic Brain Injury; Veterans; Vietnam; War; Work; chronic pain; clinically significant; cohort; gene environment interaction; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; improved; member; novel; programs; risk variant; rurality; screening; sexual trauma; suicidal behavior; suicidal morbidity; suicidal risk

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.

平均每天有 18 名退伍军人自杀。事实上，从 2009 年到 2018 年，已有超过 64,000 名退伍军人死亡。 自杀人数与越南战争造成的美军死亡人数大致相同， 伊拉克和阿富汗的自杀想法和行为的遗传率估计范围为 30- 55%，自杀的遗传基础在很大程度上仍然未知。我们的研究团队领导并参与了这项研究。 迄今为止，许多关于自杀想法和行为的最大的全基因组关联研究（GWAS）， 包括在退伍军人和军事样本中进行的每一次最大的研究。 对参加百万退伍军人计划的超过 400,000 名退伍军人进行自杀未遂 GWAS 计划（MVP）。这项研究确定了多个泛种族和血统特异性的全基因组显着位点。 此外，路径分析发现了与退伍军人尝试自杀的风险相关的证据。 许多具有高度临床意义的生物途径的过度表达，包括催产素信号传导， 谷氨酸能突触、皮质醇合成和分泌、多巴胺能突触和昼夜节律。 与此同时，我们一直在研究一系列导致自杀想法和行为的环境风险因素 退伍军人，如性创伤、创伤后应激障碍、抑郁、药物滥用障碍、边缘人格 疾病、慢性疼痛、创伤性脑损伤和睡眠障碍（等等）我们也积极采取措施。 努力识别新的环境风险因素，包括地理空间因素[例如社会经济地位 （SES），农村]，其中许多以前没有在大规模的自杀基因研究中得到检验 我们认为，要完全了解复杂的表型，就需要了解相关的风险。 遗传风险因素、相关环境风险因素以及这些风险因素相互作用的方式。 因此，在我们研究计划的下一阶段，我们建议进行最大的基因- 迄今为止，这项工作将针对自杀想法和行为进行环境全基因组相互作用研究（GEWIS）。 使我们能够找到新的方法来改进高风险退伍军人的识别，同时也大大增加 我们对自杀的生物学基础的理解我们的长期目标是开发有效的筛查和治疗方法。 减少退伍军人自杀和自杀行为发生率的干预策略。 这个特定应用的目标是发现新颖的、可复制的 GxE 交互，从而提高退伍军人的 这项研究的基本原理是识别遗传变异， 与自杀想法和行为可靠相关的环境因素和 GxE 相互作用 可能会导致更好地识别高风险退伍军人，并发现更多具有临床意义的信息 这些发现反过来可能导致新的、改进的治疗和预防。 在目标 1 中，我们将确定与以下因素最密切相关的环境风险因素。 在目标 2 中，我们将讨论 MVP 群体中自杀未遂、自杀意念和自杀死亡的发生情况。 开展迄今为止最大规模的自杀想法和行为 GEWIS，以确定新颖、可复制的 GxE 目标 3 中退伍军人自杀企图、自杀意念和自杀死亡的相互作用的预测。 为了评估我们研究结果的临床效用，我们将与我们的运营合作伙伴合作，以确定是否 添加我们的首要遗传风险因素、环境风险因素和 GxE 相互作用可提高预测结果 健康退伍军人康复参与和协调强化治疗 (REACH VET) 的效用 MVP 队列中的自杀风险算法从拟议的工作中获得的结果可以从根本上解决。 转变对自杀生物学的理解，带来新的和改进的治疗方法，并改善 VA 的努力 识别并干预有自杀风险的退伍军人因此，本申请具有巨大的意义。 推进退伍军人事务部使命并改善退伍军人健康、安全和福祉的潜力。