Sex hormones and post-traumatic stress disorder (PTSD)

性激素和创伤后应激障碍（PTSD）

• 批准号: 10629383
• 负责人: Laramie Duncan
• 金额: $ 39.46万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629383
• 关键词: Adult; Age; American; Animals; Anxiety; Anxiety Disorders; Awareness; Biological; Biological Markers; Budgets; Clinical Treatment; Clinical Trials; Cognitive; Contraceptive Agents; Data; Development; Disease; Drug Prescriptions; Elements; Epidemic; Estradiol; Etiology; Exclusion; Fright; Future; Genetic; Genetic study; Gonadal Steroid Hormones; Grant; Health Status; Healthcare; Hereditary Disease; Hormones; Hydrocortisone; Individual; Investigation; Knowledge; Learning; Life; Link; Machine Learning; Measurement; Measures; Medical; Medical History; Menstrual cycle; Menstruation; Mental Depression; Mental Health; Mental disorders; Methods; Military Personnel; Modeling; Outcome; Participant; Persons; Pharmaceutical Preparations; Phenotype; Play; Population Heterogeneity; Post-Traumatic Stress Disorders; Postmenopause; Prevalence; Prevention; Prevention strategy; Proxy; Public Health; Research; Research Design; Role; Sample Size; Sampling; Sampling Studies; Sex Differences; Techniques; Testing; Testosterone; Time; Trauma; United States; United States National Institutes of Health; Woman; Work; biobank; experience; genome wide association study; genomic locus; inter-individual variation; loved ones; men; military service; novel; novel therapeutic intervention; precision medicine; psychiatric genomics; public health relevance; reproductive; service member; sex; treatment strategy

Project summary The untreated burden of post-traumatic stress disorder (PTSD) in the United States is a massive contributor to healthcare budgets in both the military and civilian sectors, and better treatment and prevention methods are needed. Fortunately, awareness of PTSD among military service members has grown in recent years, and yet, there is a hidden epidemic of PTSD among civilians and women. Women experience PTSD at about twice the rate of men (11% vs. 5%), but the causes for this sex difference are largely unknown. It has long been suspected that sex hormones play a major role in development of – and also potentially protection from – PTSD and other mental health disorders. This project will provide the largest ever study of sex hormone effects on PTSD and the related mental health outcomes of depression and anxiety disorders. Whereas studies in the past were limited by small sample sizes and results were inconclusive, this investigation will use a massive sample size of approximately 500,000 participants to answer questions about two well-known sex hormones (testosterone and estradiol) and three psychiatric outcomes (PTSD, depression, and anxiety disorders). These variables were measured in the UK Biobank, and we have been granted access to the data to study sex hormone effects on mental health outcomes and to study genetic effects underlying both sex hormone levels and mental health disorders. The completion of this work will reveal whether rates of mental health disorders vary with testosterone and estradiol levels. It may be the case that levels of hormones that are both too high and too low are problematic. Given this reality, we will use sophisticated regression and machine learning techniques, and therefore we will be able to detect linear and non-linear relationships between sex hormones and PTSD, depression, and anxiety disorders. The sample size and study design make this the most powerful study conducted to date, and the results will be generalizable to diverse populations. In addition to the outcomes mentioned above, we will further explore genetic effects underlying relationships between sex hormones and mental health disorders. To do this, we will conduct genome-wide association studies (GWAS) of both testosterone and estradiol. We will then make polygenic scores for testosterone and estradiol, yielding genetic proxies of sex hormone levels which can be used in studies in which sex hormones have not been measured. Finally, we will test for shared genetic effects between genetic effects on sex hormones and genetic effects on psychiatric disorders in order to better understand the etiology of these common, debilitating, and inadequately treated mental health disorders. Taken together, these findings will provide critical foundational knowledge relevant to clinical trials which are currently testing testosterone and estradiol as treatments for PTSD, depression, and anxiety disorders. These results will also provide actionable findings for the development of novel treatment and prevention strategies.

项目概要 在美国，未经治疗的创伤后应激障碍（PTSD）负担是导致 军事和民用部门的医疗保健预算以及更好的治疗和预防方法 幸运的是，近年来，军人对创伤后应激障碍的认识有所提高，并且 然而，创伤后应激障碍在平民和女性中存在着隐性流行。女性患创伤后应激障碍的比例约为两倍。 男性的比例（11% vs. 5%），但这种性别差异的原因长期以来一直未知。 怀疑性激素在发育过程中发挥着重要作用，并且还具有潜在的保护作用 该项目将提供有史以来最大规模的性激素研究。 对 PTSD 以及抑郁症和焦虑症相关心理健康结果的影响。 过去的研究受到样本量较小的限制，结果尚无定论，本次调查将使用 约 500,000 名参与者的庞大样本量，回答有关两种众所周知的性别的问题 激素（睾酮和雌二醇）和三种精神结局（创伤后应激障碍（PTSD）、抑郁症和焦虑症） 这些变量是在英国生物银行测量的，我们已被授予访问数据的权限。 研究性激素对心理健康结果的影响，并研究两性的遗传效应 这项工作的完成将揭示激素水平和心理健康障碍的发生率。 健康障碍随睾酮和雌二醇水平的不同而变化。 太高和太低都是有问题的，考虑到这一现实，我们将使用复杂的回归和 机器学习技术，因此我们将能够检测线性和非线性关系 性激素与创伤后应激障碍、抑郁症和焦虑症之间的关系 样本量和研究设计。 使这项研究成为迄今为止最有力的研究，其结果将推广到不同的领域 除了上述结果外，我们还将进一步探讨潜在的遗传效应。 为此，我们将进行全基因组研究。 然后我们将为睾酮和雌二醇进行多基因评分。 睾酮和雌二醇，产生性激素水平的遗传代理，可用于以下研究 最后，我们将测试遗传之间的共同遗传效应。 对性激素的影响以及对精神疾病的遗传影响，以便更好地了解病因 总而言之，这些常见的、使人衰弱且治疗不当的精神健康疾病。 研究结果将提供与目前正在测试的临床试验相关的关键基础知识 睾酮和雌二醇作为治疗创伤后应激障碍、抑郁症和焦虑症的药物也将得到这些结果。 为制定新的治疗和预防策略提供可行的发现。

项目成果

Polygenic scores for psychiatric disorders in a diverse postmortem brain tissue cohort.

• DOI: 10.1038/s41386-022-01524-w
• 发表时间: 2023-04
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Duncan, Laramie;Shen, Hanyang;Schulmann, Anton;Li, Tayden;Kolachana, Bhaskar;Mandal, Ajeet;Feng, Ningping;Auluck, Pavan;Marenco, Stefano
• 通讯作者: Marenco, Stefano

Are novel treatments for brain disorders hiding in plain sight?

脑部疾病的新疗法是否隐藏在众目睽睽之下？

• DOI: 10.1038/s41386-023-01636-x
• 发表时间: 2024
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Duncan,Laramie;Deisseroth,Karl
• 通讯作者: Deisseroth,Karl

Shared genetic influences on depression and menopause symptoms.

• DOI: 10.1017/s0033291721004037
• 发表时间: 2023-04
• 期刊: PSYCHOLOGICAL MEDICINE
• 影响因子: 6.9
• 作者: Meijsen, Joeri J.;Shen, Hanyang;Vemuri, Mytilee;Rasgon, Natalie L.;Koenen, Karestan C.;Duncan, Laramie E.
• 通讯作者: Duncan, Laramie E.

Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan.

小脑颗粒细胞在整个生命周期中形成非神经元 3D 基因组结构。

• DOI: 10.1101/2023.02.25.530020
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Tan,Longzhi;Shi,Jenny;Moghadami,Siavash;Wright,CydneyP;Parasar,Bibudha;Seo,Yunji;Vallejo,Kristen;Cobos,Inma;Duncan,Laramie;Chen,Ritchie;Deisseroth,Karl
• 通讯作者: Deisseroth,Karl