Genetic and Molecular Determinants 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。这些危险因素中最一致的是精神疾病的存在。制定自杀预防战略所固有的挑战之一是，自杀是一种罕见和不可预测的事件。因此，非常重要的是，确定与自杀高风险相关的生物标记家庭、双胞胎和收养研究强烈表明基因对自杀有贡献；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。到目前为止，已经进行了许多常规的关联研究，但还没有发现任何可以作为自杀风险可靠预测因素的基因变异。在这项申请中，我们建议使用替代方法，我们预计这些方法在识别此类预测因素方面会更成功。我们的第一种方法(将在特定目标1中探索)与一种很少研究的稳态可塑性机制有关-5-HT2CR的RNA编辑。编辑可以产生许多不同的5-HT2CR亚型，这些亚型的功能活性不同，从而使表达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，自杀受害者的前额叶皮质(PFC)中的5-HT2CR编辑发生了改变，与他们潜在的精神疾病无关。因此，编辑的失调构成了与完全自杀密切相关的生物因素。5-HT2CR的表达水平只能在大脑和脊髓中可靠地检测到。因此，编辑不能在与自杀相关的区域(即PFC)的活体个体中进行非侵入性测量。我们假设存在与5-HT2CR编辑相关的单核苷酸多态(SNPs)，在我们的初步研究中，我们已经确定了几个这样的候选SNPs。在这里，我们的目标是证实这些发现，并在显著更大的尸检样本队列(N=583)中识别与编辑相关的新SNPs。与编辑相关的SNPs可以作为衡量大脑编辑的指标，因此，可以作为自杀风险的预测指标。我们的第二个方法(具体目标2)将是发现与构成自杀易感因素的行为特征相关的SNPs，因此被认为代表与自杀相关的内表型。这一策略允许将自杀解构成病因和基因异质性较低的部分。为此，我们将在一个庞大的队列(N=1,200)中进行全基因组关联研究(GWAS)，这些队列中的年轻男性在人口统计学上和基因上都是相同的。对于这些人，已经获得了自杀相关表型的自我报告措施和行为/心理生理学评估的结果，以及基因组DNA样本，并可供我们使用。并不是所有与编辑或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和目标2中确定的哪些SNP更有可能代表自杀特有的风险因素。为了实现这一目标，我们将使用(1)大量公开可用的GWAS数据集，这些数据集适用于患有 无自杀未遂史和(2)死于自杀或其他方式的精神病人的死后PFC标本。一旦得到确认，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关联。绘制这些等位基因的图谱还将发现有自杀倾向的人大脑中发生变化的路径，从而为理解自杀的病理生理学开辟了新的场所。

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.