Deciphering the role of neuronal and peripheral DNA methylation in suicide and bipolar disorder

项目摘要/摘要 预防自杀行为，特别是在有情绪障碍的患者中，是精神疾病中最重要的 健康专业人士。影响大约1%-2%人口的双相情感障碍(BD)患者尤其 有自杀行为的高风险，25%-50%的患者一生中至少有一次自杀企图。在……里面 此外，尽管有证据表明BD和自杀有共同的遗传风险，而且压力可能在自杀中发挥关键作用， 一些患者比其他患者更容易发生自杀行为的机制目前还不得而知。引导式 根据强有力的初步数据，我们假设包括DNA甲基化在内的表观遗传机制可能是自杀的基础 BD患者的风险。此外，DNA甲基化标记物可能为临床提供相关的生物标记物。 确定自杀行为风险最高的患者。这些假设将通过完成三个具体的 目标。在目标1中，我们将使用最新一代的光甲基化EPIC来表征DNA甲基化的变化 BeadChip 850K平台在发现死后背外侧前额叶皮质神经元样本中的应用 来自自杀或死于其他原因和对照的BD患者。有希望的标记将通过以下方式进行验证 氧化亚硫酸氢盐焦磷酸测序，并通过途径分析进一步探索。在目标2中，我们将调查协调的 死前额叶皮质中BD和自杀未遂的遗传风险及DNA甲基化改变之间的变化 使用与Aim 1相同的队列和来自UTHealth Brain Collection的复制队列进行精神病学研究 精神错乱。在目标3中，我们将分析自杀的甲基组标记物的临床相关性。 与健康对照组相比，曾试图自杀或没有自杀的成年BD患者 可获得包含人口统计学、临床和神经解剖学数据以及全基因组数据的综合数据集 甲基化和基因分型数据。将进一步探索预测自杀行为的具体目标和途径 先进的统计和生物信息学工具，同时控制已知与自杀风险相关的协变量， 随后开发了用于在个人层面预测自杀的机器学习算法。的 请注意，K01的首要目标是进一步加强PI在自杀的生物学和临床方面的专业知识， 生物信息学、尸检分析和表观基因组学，这将确保为启动奠定坚实的方法学基础 精神病学表观遗传学的独立实验室。重要的是，一群强大的导师和合作者具有非凡的 在培训初级教员方面的记录已被选中，以在颁奖期间提供智力和技术投入。 此外，德克萨斯大学杰出的资源、设施和多学科科学社区 休斯顿健康科学中心和德克萨斯医疗中心代表着一个理想的环境，以确保PI 完成了他的研究和职业目标。这项提议与NIMH的使命很好地结合在一起，它不会 不仅为PI提供过渡到完全独立所需的关键培训，而且还解决重要的、可测试的问题 关于BD患者自杀风险知之甚少以及缺乏特定工具的问题 识别易受攻击的对象。

Project Summary/Abstract Prevention of suicidal behavior, especially among patients with mood disorders, is of uttermost importance among mental health professionals. Patients with bipolar disorder (BD), which affects around 1-2% of the population, are at a particularly high risk for developing suicidal behavior, with 25-50% of patients making at least one suicide attempt in their lifetime. In addition, although there is evidence that BD and suicide share a genetic risk and that stress may play a key role in suicidality, the mechanisms by which some patients are more vulnerable to suicidal behavior than others are vastly unknown. Guided by strong preliminary data, we hypothesize that epigenetic mechanisms, including DNA methylation, may underlie suicide risk among BD patients. Moreover, DNA methylation markers may provide clinically-relevant biomarkers for the identification of patients at highest risk for suicidal behavior. These hypotheses will be tested by completing three specific aims. In Aim 1, we will characterize DNA methylation alterations with the latest-generation Illumina MethylationEPIC BeadChip 850K platform in a discovery sample of neurons isolated from post-mortem dorsolateral prefrontal cortex tissues from patients with BD that committed suicide or died of other causes and controls. Promising markers will be validated by oxidative bisulfite pyrosequencing and further explored by pathway analyses. In Aim 2, we will investigate the coordinated changes between genetic risk for BD and suicide attempt and DNA methylation alterations in post-mortem prefrontal cortex using the same cohort as Aim 1 and a replication cohort from the UTHealth Brain Collection for Research in Psychiatric Disorders. In Aim 3, we will analyze the clinical correlates of methylome markers of suicide in an independent cohort of adult patients with BD that have previously attempted to commit suicide or not, compared to healthy controls, from which a comprehensive dataset with demographic, clinical, and neuroanatomical data is available, as well as genome-wide methylation and genotyping data. Specific targets and pathways predicting suicidal behavior will be further explored by sophisticated statistics and bioinformatics tools while controlling for co-variables known to associate with suicidal risk, followed by the development of machine learning algorithms for the prediction of suicidality at the individual level. Of note, the overarching goal of this K01 is to further the PI’s expertise in the biology and clinical aspects of suicide, bioinformatics, post-mortem analyses, and epigenomics, which will ensure a methodologically strong foundation to launch an independent lab in psychiatric epigenetics. Importantly, a strong group of mentors and collaborators with a remarkable track record in training junior faculty has been selected to provide intellectual and technical input during the award period. In addition, the outstanding resources, facilities, and multidisciplinary scientific community at the University of Texas Health Science Center at Houston and the Texas Medical Center represent an ideal environment to ensure that the PI accomplishes his research and career objectives. This proposal is well aligned with the mission of the NIMH, and it will not only provide the PI with crucial training required to his transition to full independence, but also address important, testable questions regarding the poorly understood risk for suicide among BD patients and the lack of specific tools for the identification of vulnerable subjects.