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名退伍军人死于自杀。实际上，从2009年到2018年，有64,000多名退伍军人死亡 通过自杀，这与越南战争造成的美国军事死亡人数大致相同 伊拉克和阿富汗合并。而自杀思想和行为的遗传力估计范围为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加了 迄今为止，许多最大的全基因组关联研究（GWAS），迄今为止的自杀思想和行为 包括每个在退伍军人和军事样本中进行的最大的。我们最近的工作涉及 在有40万名退伍军人的退伍军人中进行了40万名退伍军人的自杀企图 程序（MVP）。这项研究确定了多个泛种族和祖先特异性基因组明显的基因座 与在退伍军人中自杀的风险有关。此外，途径分析发现了 对许多具有高临床意义的生物学途径的过度代表，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。在 相似，我们一直在研究自杀思想和行为的广泛环境风险因素 在退伍军人中，例如性创伤，PTSD，抑郁症，药物使用障碍，边缘性格 疾病，慢性疼痛，脑损伤和睡眠障碍（等）。我们也积极 努力确定新的环境风险因素，包括地理空间因素[例如，社会经济地位 （SES），粗糙度]，其中许多以前尚未在自杀的大规模遗传研究中检查 风险。我们认为，对复杂表型的完全理解需要了解相关的 遗传风险因素，相关的环境风险因素以及这些危险因素相互作用的方式。 彼此之间，在我们的研究计划的下一阶段，我们建议进行最大的基因 迄今为止，自杀思想和行为的环境基因组相互作用研究（GEWIS）。这项工作将 使我们能够确定改善高风险退伍军人识别的新方法，同时也大大增加 我们对自杀的生物基础的理解。我们的长期目标是制定有效的筛选和 减少退伍军人自杀和自杀行为的干预策略。总体 该特定应用的目的是发现增加退伍军人的新颖，可复制的GXE相互作用 自杀思想和行为的风险。这项研究的理由是鉴定遗传变异， 环境因素和与自杀思想和行为可靠相关的GXE相互作用 可能导致改善高风险退伍军人的识别，并发现其他临床上的疾病 生物途径。这样的发现反过来可能导致新的和改进的治疗和预防 方法。在AIM 1中，我们将确定与 在AIM 2中，我们将发生自杀企图，自杀念头和MVP队列中的自杀死亡。 迄今 在退伍军人中预测自杀企图，自杀思想和自杀死亡的相互作用。在AIM 3中 为了评估我们发现的临床实用性，我们将与我们的运营伙伴合作，以确定是否是否 加入我们的顶级遗传危险因素，环境风险因素和GXE相互作用提高了预测 卫生退伍军人增强治疗的恢复和协调的效用 MVP队列内的自杀风险算法。从拟议的工作中获得的发现可以从根本上 转移对自杀生物学的理解，导致新的和改进的治疗方法，并改善了VA的努力 识别并干预有自杀风险的退伍军人。因此，本应用程序具有巨大的 潜力提高VA的使命并改善退伍军人的健康，安全和福祉。