Harnessing advances in the genetics of suicidality to identify and dissect psychosocial pathways to risk

利用自杀遗传学的进展来识别和剖析风险的心理社会途径

• 批准号: 10419131
• 负责人: ALEXIS C EDWARDS
• 金额: $ 58.09万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419131
• 关键词: Address; Adolescence; Adult; Area; Behavioral; Behavioral Mechanisms; Biological; Candidate Disease Gene; Cessation of life; Characteristics; Child Abuse; Childhood; Clinical; Complement; Complex; Data; Development; Disease; Divorce; Environmental Exposure; Environmental Risk Factor; Epidemiology; Etiology; Exposure to; Family; Family Study; Feeling suicidal; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Heritability; Impulsive Behavior; Individual; Intervention; Investigation; Knowledge; Life Cycle Stages; Longevity; Major Depressive Disorder; Mediating; Mediation; Mediator of activation protein; Medical; Mental Depression; Mind; Modeling; Molecular; Molecular Genetics; Nature; Outcome; Pathway interactions; Phenotype; Population Study; Public Health; Publishing; Recording of previous events; Registries; Research; Risk; Risk Assessment; Risk Factors; Sample Size; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Socioeconomic Status; Specificity; Suicide; Suicide attempt; Testing; Time; Twin Multiple Birth; Twin Studies; abuse neglect; analytical method; base; behavioral disinhibition; behavioral outcome; comorbidity; data registry; depressive symptoms; externalizing behavior; family genetics; genome wide association study; ideation; improved; insight; phenotypic data; psychologic; psychosocial; statistics; suicidal; suicidal behavior; suicidal morbidity; suicidal risk

Project Summary Suicidal thoughts and behaviors (STB) are substantially impacted by genetic factors. However, molecular genetic studies of suicidality, and their genetically informative epidemiologic counterparts, have historically been statistically underpowered, precluding substantive interpretation of the effects of genetic influences in a developmental or psychosocial context. Recent advances include well-powered genomewide association studies alongside twin/family modeling of Swedish national registry data on (non-fatal) suicide attempt and death. The clear signals observed in these studies provide initial insight to the genetic etiology of suicidality, including: (i) suicide attempt and death are substantially, but not entirely, genetically correlated, raising the possibility that genetic liability underlying these distinct outcomes may be differentially related to risk pathways; (ii) the qualitative and quantitative nature of genetic liability to suicidality shifts across the life course; and (iii) genetic influences underlying suicidality are likely related to multiple behavioral correlates of risk, notably behavioral disinhibition and depression. Additional gene identification studies are essential to further elucidate the molecular nature of suicidality. However, to fully characterize how genetic liability manifests into STB, gene-finding studies must be complemented by research efforts that address the relationship between aggregate genetic risk and distinct STB outcomes, STB occurring during different periods of development (e.g., adolescence versus adulthood), key behavioral mediators, and environmental precipitants. The current proposal will address this critical knowledge gap through the incorporation of aggregate genetic risk scores for suicide attempt or death into models of psychosocial risk for STB. We will implement our research aims in a range of target samples selected for the unique perspectives they enable: (i) They span the life course, from childhood to late adulthood (and through death in the case of national Swedish registries); (ii) several include longitudinal assessments; (iii) they are densely phenotypically characterized, with data available on multiple STB (e.g., ideation, plans, attempts), behavioral mediators, and environmental risk factors; and (iv) they include five population-based studies, enabling us to expand our understanding of STB etiology outside of highly selected samples, along with two samples ascertained for history of major depression, enabling us to assess whether pathways of risk to STB are consistent across groups, and whether genetic liability to suicidality is superseded by the powerful clinical context of depression. The assembled team’s complementary areas of expertise are ideally suited to successfully implement the research aims. The proposed analyses leverage the aforementioned recent advances in the genetics of suicidality while enabling unparalleled and critical context for understanding the complex and dynamic pathways to suicidal thoughts and behaviors.

项目摘要 自杀思想和行为（STB）受到遗传因素的实质影响。但是，分子 自杀的遗传研究及其遗传信息的流行病学对应物在历史上具有 统计学上的能力不足，排除了对遗传影响影响的实质性解释 发展或社会心理环境。最近的进步包括全基因组的关联 与瑞典国家注册表的双胞胎/家庭建模一起研究（非致命）自杀企图和 死亡。这些研究中观察到的明显信号为自杀遗传学学的初步见解， 包括：（i）自杀企图和死亡基本上是但并非完全相关的 这些不同结果的遗传责任的可能性可能与风险途径不同。 （ii）遗传责任对自杀的定性和定量性质在整个生活过程中转移； （iii） 遗传影响潜在的自杀性可能与多种行为相关性有关，著名 行为抑制和抑郁。其他基因鉴定研究对于进一步阐明至关重要 自杀的分子性质。但是，为了充分表征遗传责任如何表现为STB 基因调查研究必须通过研究工作来完成，以解决 总遗传风险和不同的STB结果，STB发生在不同的发育时期（例如， 青少年与成年期，关键的行为介体和环境沉淀物。电流 提案将通过纳入总遗传风险评分来解决这一关键知识差距 自杀企图或死亡，成为STB的心理社会风险模型。我们将实施我们的研究目标 为其启用的独特视角选择的目标样本范围：（i）它们跨越生命课程，从 童年至成年后期（在瑞典国家登记处死亡）； （ii）一些包括 纵向评估； （iii）它们具有表型表征，并在多个上获得数据 STB（例如，构思，计划，尝试），行为调解人和环境风险因素； （iv）他们 包括五项基于人群的研究，使我们能够扩大对STB病因的理解。 高度选择的样本，以及两个样本确定了重度抑郁史的历史，使我们能够 评估STB的风险途径是否在各组之间保持一致，以及是否对 自杀性被强大的抑郁症临床背景所取代。组装团队的完整性 专业知识领域非常适合成功实施研究目的。提出的分析 利用自杀遗传学的最新进展，同时实现无与伦比的和 理解自杀思想和行为的复杂和动态途径的关键背景。