Genetic and Molecular Determinants of Suicide

自杀的遗传和分子决定因素

• 批准号: 8974291
• 负责人: STELLA DRACHEVA
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974291
• 关键词: Address; Adoption; Alleles; Antidepressive Agents; Area; Autopsy; Behavioral; Biological; Biological Assay; Biological Factors; Biological Markers; Blood Cells; Brain; Classification; Cognitive Therapy; Complex; Country; Data Set; Economics; Event; Family; Frequencies; Functional disorder; Gender; General Population; Genes; Genetic; Genetic Polymorphism; Genomic DNA; Goals; Greek; Health; Healthcare; Individual; Intervention; Laboratories; Life; Link; Maps; Measures; Mental disorders; Molecular Genetics; Neurons; Pathway interactions; Patient Self-Report; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Prefrontal Cortex; Protein Isoforms; Proxy; Psyche structure; Psychophysiology; RNA; RNA Editing; Recording of previous events; Risk; Risk Factors; Sampling; Serotonin Receptor 5-HT2C; Single Nucleotide Polymorphism; Social support; Specificity; Specimen; Spinal Cord; Suicide; Suicide attempt; Suicide prevention; System; Twin Multiple Birth; Unemployment; Veterans; Vulnerable Populations; accomplished suicide; behavior measurement; cohort; combat; endophenotype; genetic risk factor; genetic variant; genome wide association study; genome-wide analysis; high risk; interest; male; molecular marker; novel; operation; psychologic; risk variant; social; suicidal behavior; suicidal risk; suicide rate; suicide victim; trait

DESCRIPTION (provided by applicant): Suicide is a complex phenomenon comprised of biological and psychological risk factors, in addition to social, environmental, and economic contributors. The most consistent of these risk factors is the presence of a psychiatric illness. One of the challenges inherent in developing strategies for suicide prevention is that suicide is a rare and unpredictable event. It is extremel important, therefore, to identify biological markers that are associated with high risk for suicide Family, twin and adoption studies strongly suggest genetic contributions to suicide; furthermore, the genetic predilection for suicide appears to be largely independent of genetic liability to mental illness. To date, many conventional association studies have been performed but have not revealed any genetic variants that could be used as reliable predictors of suicide risk. In thi application we propose using alternate approaches which we expect to be more successful in identifying such predictors. Our first approach, (which will be explored in Specific Aim 1) is related to a rarely studied mechanism of homeostatic plasticity-RNA editing of serotonin 2C receptor (5-HT2CR). Editing can generate many different 5-HT2CR isoforms which vary in their functional activity, thus enabling the 5-HT2CR-expressing neurons to respond to both environmental and genetic perturbations. Our studies, as well as studies in other laboratories, have demonstrated that 5-HT2CR editing is altered in the prefrontal cortex (PFC) of suicide victims regardless of their underlying psychiatric illness. Thus, dysregulation of editing constitutes a biological factor that is strongly associated with completed suicide. 5-HT2CR is expressed at levels that can be reliably assayed only in the brain and spinal cord. Therefore, editing cannot be noninvasively measured in living individuals in the areas relevant to suicide (i.e., PFC). We hypothesize the existence of single nucleotide polymorphisms (SNPs) that are associated with 5-HT2CR editing, and in our preliminary studies we have already identified several such candidate SNPs. Here we aim to confirm these findings and to identify novel editing-associated SNPs in a significantly larger cohort of postmortem specimens (N=583). The editing-associated SNPs can be used as a proxy for measuring editing in the brain, and therefore, as predictors for suicide risk. Our second approach (Specific Aim 2) will be to uncover SNPs that are associated with behavioral traits that constitute susceptibility factors for suicide and are, therefore, considered to represent suicide-related endophenotypes. This strategy allows the deconstruction of suicide into parts that are less etiologically and geneticall heterogeneous. To this end, we will perform genome-wide association studies (GWASs) in a large cohort (N=1,200) of demographically and genetically homogeneous young male conscripts in the Greek Army. For these individuals the results of self-reporting measures and behavioral/psychophysiological assessments of suicide-related phenotypes, as well as genomic DNA specimens, have already been obtained and are available for us. Not all genetic components that are associated with editing or with suicide-related endophenotypes are specifically related to suicide. Therefore, in our last Aim we will determine which of the SNPs identified in Aims 1 and 2 are more likely to represent suicide-specific risk factors. To achieve this goal, we will use (1) large publicly available data sets of GWASs in psychiatric patients with and without a history of attempted suicide and (2) postmortem PFC specimens from psychiatric patients who died of suicide or by other means. When confirmed, the risk alleles could be measured in peripheral blood cells, thus providing biological correlates associated with liability to suicide. Mapping these alleles will also uncover pathways that are altered in the brains of people who are prone to suicidal behavior, hence opening new venues to the understanding of pathophysiology of suicide.

描述（由申请人提供）： 自杀是一种复杂的现象，除了社会，环境和经济贡献者外，还包括生物学和心理危险因素。这些危险因素中最一致的是存在精神病。制定预防自杀战略固有的挑战之一是，自杀是罕见且无法预测的事件。因此，重要的是要确定与自杀家族，双胞胎和收养研究高风险相关的生物学标志物强烈建议对自杀的遗传贡献；此外，自杀的遗传偏见似乎在很大程度上与精神疾病的遗传责任无关。迄今为止，已经进行了许多常规关联研究，但尚未揭示任何可以用作自杀风险可靠预测指标的遗传变异。在应用程序中，我们建议使用替代方法，我们期望在识别此类预测因子方面更加成功。 我们的第一种方法（将在特定目标中进行探讨）与很少研究的脑稳态可塑性-RNA编辑的机制有关，羟色胺2C受体（5-HT2CR）。编辑可以产生许多不同的5-HT2CR同工型，它们的功能活性各不相同，从而使5-HT2CR的神经元能够对环境和遗传扰动做出反应。我们的研究以及其他实验室的研究表明，在自杀受害者的前额叶皮层（PFC）中，无论其潜在的精神疾病如何，都会改变5-HT2CR编辑。因此，编辑的失调构成了与完成自杀密切相关的生物学因素。 5-HT2CR以可以可靠地测定的水平表达，只有在大脑和脊髓中。因此，在与自杀相关的地区（即PFC）的生物中，编辑不能无创测量。我们假设与5-HT2CR编辑相关的单核苷酸多态性（SNP）的存在，在我们的初步研究中，我们已经确定了几个此类候选SNP。在这里，我们的目的是确认这些发现并在明显更大的验尸标本中确定新型编辑相关的SNP（n = 583）。与编辑相关的SNP可以用作测量大脑编辑的代理，因此可以用作自杀风险的预测因素。 我们的第二种方法（特定目的2）将是发现与构成自杀易感性因素的行为性状相关的SNP，因此被认为代表自杀相关的内型型。该策略允许将自杀解构为病因和遗传异质的部分。为此，我们将在希腊军队中的人口统计学和遗传上的年轻男性应征入伍（n = 1,200）中进行全基因组协会研究（GWASS）。对于这些人来说，已经获得了自杀相关表型的自我报告措施和行为/心理生理评估的结果，以及基因组DNA标本的结果，已经获得并为我们提供了。 并非所有与编辑或与自杀相关的内表型相关的遗传成分都与自杀特别相关。因此，在我们的最后一个目标中，我们将确定目标1和2中确定的哪些SNP更可能代表特定于自杀的风险因素。为了实现这一目标，我们将使用（1）精神病患者的大量公开数据集GWASS 并且没有未遂自杀的病史和（2）死后死于自杀或其他手段的精神病患者的验尸PFC标本。 确认后，可以在外周血细胞中测量风险等位基因，从而提供与自杀责任相关的生物学相关。映射这些等位基因还将发现容易自杀行为的人的大脑中改变的途径，从而为理解自杀病理生理学的新场地开辟了新的场所。