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

项目摘要 自杀想法和行为（STB）在很大程度上受到遗传因素的影响。然而，分子 自杀倾向的遗传学研究，以及它们的遗传信息流行病学同行， 统计上的力量不足，排除了对遗传影响的实质性解释， 发展或心理社会背景。最近的进展包括强大的全基因组关联 研究以及瑞典国家登记处关于（非致命性）自杀企图的双胞胎/家庭模型， 死亡在这些研究中观察到的明确信号为自杀的遗传病因学提供了初步的见解， 包括：（i）自杀企图和死亡在很大程度上，但不完全，遗传相关，提高了 这些不同结果背后的遗传责任可能与风险途径存在差异; (ii)自杀倾向的遗传易感性的质和量的性质在整个生命过程中发生变化;以及（iii） 潜在自杀倾向的遗传影响可能与多种行为风险相关，特别是 行为去抑制和抑郁症。额外的基因鉴定研究对于进一步阐明 自杀的分子本质然而，为了充分描述遗传易感性如何体现在STB中， 基因发现研究必须辅之以解决以下问题的研究努力： 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， 青春期与成年期），关键行为介质和环境沉淀物。当前 该提案将通过纳入以下方面的综合遗传风险评分来解决这一关键的知识差距： 自杀未遂或死亡的模式为STB的心理社会风险。我们将以一种 一系列的目标样本选择的独特视角，他们使：（一）他们跨越生命历程，从 儿童期至成年晚期（以及在瑞典国家登记处的情况下直至死亡）;（二）一些包括 纵向评估;（iii）它们具有密集的表型特征，可获得多个 STB（例如，构思，计划，尝试），行为中介，和环境风险因素;和（iv）他们 包括五项基于人群的研究，使我们能够扩展我们对STB病因学的理解， 高度选择的样本，沿着两个确定为重度抑郁症病史的样本，使我们能够 评估STB的风险途径是否在各组之间一致，以及是否存在遗传易感性， 自杀倾向被抑郁症的强大临床背景所取代。团队的互补性 专业领域非常适合成功实现研究目标。拟议的分析 利用上述自杀遗传学方面的最新进展， 理解自杀想法和行为的复杂和动态途径的关键背景。

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.