Genetic and Molecular Determinants of Suicide

自杀的遗传和分子决定因素

• 批准号: 8774539
• 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/8774539
• 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; 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; public health relevance; 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、环境和经济因素外，还包括生物和心理风险因素。这些风险因素中最一致的是精神疾病的存在。制定自杀预防策略所固有的挑战之一是自杀是一种罕见且不可预测的事件。因此，确定与自杀高风险相关的生物学标记是非常重要的。家庭、双胞胎和收养研究强烈表明遗传对自杀的贡献;此外，自杀的遗传倾向似乎在很大程度上独立于精神疾病的遗传易感性。迄今为止，已经进行了许多传统的关联研究，但尚未发现任何可用作自杀风险可靠预测因子的遗传变异。在本申请中，我们提出使用替代方法，我们期望这些方法在识别此类预测因子方面更成功。 我们的第一种方法（将在具体目标1中探讨）与一种很少研究的稳态可塑性机制有关-血清素2C受体（5-HT 2CR）的RNA编辑。编辑可以产生许多不同的5-HT 2CR亚型，这些亚型的功能活性不同，从而使表达5-HT 2CR的神经元能够对环境和遗传干扰做出反应。我们的研究，以及其他实验室的研究，已经证明了5-HT 2CR编辑在自杀受害者的前额叶皮层（PFC）中发生了改变，无论他们是否患有潜在的精神疾病。因此，编辑失调构成了与自杀完成密切相关的生物学因素。5-HT 2CR的表达水平仅在脑和脊髓中可以可靠地测定。因此，在与自杀相关的区域中，不能在活体个体中非侵入性地测量编辑（即，PFC）。我们假设存在与5-HT 2CR编辑相关的单核苷酸多态性（SNP），在我们的初步研究中，我们已经确定了几个这样的候选SNP。在这里，我们的目的是证实这些发现，并确定新的编辑相关的SNP在一个显着较大的队列的尸检标本（N=583）。与编辑相关的SNP可以用作测量大脑中编辑的代理，因此可以作为自杀风险的预测因子。 我们的第二种方法（具体目标2）将揭示与行为特征相关的SNP，这些行为特征构成自杀的易感因素，因此被认为是自杀相关的内在表型。这一策略允许将自杀解构为病因学和遗传学上不那么异质的部分。为此，我们将在一个大的队列（N= 1，200）的人口统计学和遗传同质的年轻男性应征入伍者在希腊军队进行全基因组关联研究（GWAS）。对于这些个体，已经获得了自我报告措施和自杀相关表型的行为/心理生理学评估结果以及基因组DNA标本，并可供我们使用。 并非所有与编辑或自杀相关的内在表型相关的遗传成分都与自杀有关。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SNP中哪些更可能代表自杀特异性风险因素。为了实现这一目标，我们将使用（1）大量公开可用的精神病患者GWAS数据集， （2）自杀或其他方式死亡的精神病患者的死后PFC标本。 一旦得到证实，就可以在外周血细胞中测量风险等位基因，从而提供与自杀倾向相关的生物学相关性。绘制这些等位基因也将揭示那些有自杀行为倾向的人大脑中发生改变的途径，从而为理解自杀的病理生理学开辟新的途径。