创伤后应激障碍的遗传易感性研究

创伤后应激障碍(PTSD)的病理生理机制还不明确．研究遗传因素作用的方式是探讨其发病机制的重要方法，并有助于采取更为有效的治疗和干预措施。本文从遗传学的角度介绍了PTSD遗传易感性方面的研究现状及展望。     

抑郁症外周血白细胞基因差异表达研究进展

抑郁症病因及发病机制尚未明确,可能是基因易感性和环境共同作用的结果。由于以往采用连锁分析方法难以确定其主要致病基因及遗传方式,因此近年来有关抑郁症的分子遗传学研究从原先在脱氧核糖核酸（DNA）水平上寻找与其有关的结构缺陷基因,发展到在核糖核酸（RNA）水平上检测与之有关的表达异常基因。目前在抑郁症的外周血细胞的基因表达上存在一些争议,     

偏头痛诱发因素与遗传

偏头痛诱发因素多种多样,每种诱因对患者的影响程度也因人而异。不同偏头痛患者对各种诱因如月经、酒精、含酚类食物、含组胺食物等的敏感性不同,遗传学研究也证实某些偏头痛诱因的确存在遗传易感性。许多基因参与了偏头痛的发病机制,也影响了包括诱因在内的某些临床特征,可能与偏头痛分型有关。针对某一诱因挑选敏感人群作为研究对象,有助于发现诱因的遗传机制,进而深入理解偏头痛的发病机理。     

HLA与重症肌无力的遗传易感性

重症肌无力的发病机制目前尚不清楚,其中对HLA基因多态性与重症肌无力遗传易感性之间的关系进行了大量研究。不同种族、性别的重症肌无力病人遗传易感性与HLA-Ⅰ、Ⅱ、Ⅲ类基因各不同位点之间存在显著相关性,其易感机制有待于进一步阐明。     

基于症状分类的创伤后应激障碍神经环路机制研究进展北大核心CSCD

创伤后应激障碍(PTSD)发病受多种因素影响,生物学机制是PTSD发病机制的重要组成,对深入理解PTSD、寻找客观的诊断标志物以及研发新型PTSD治疗药物十分重要。脑影像、光遗传及化学遗传学技术等神经科学研究技术的进展揭示了脑结构、脑功能以及神经环路改变在PTSD发病中的重要作用。但由于PTSD临床表现复杂、症状组合不同,目前未有一致性结论。因此,本综述尝试根据PTSD诊断的症状分类,从临床影像与基础环路研究两个方面归纳、总结PTSD不同症状的神经环路异常机制,从而为阐明PTSD发病机制、寻找客观生物标志物、筛选全新治疗靶点提供新的思路。     

论创伤后应激障碍的司法精神病学鉴定

目的探讨创伤后应激障碍的本质特征及司法精神病学鉴定实践中争议较大的问题。方法对PTSD诊断标准和流行病学、应激源、发病机制及共病特征进行研究,对PTSD鉴定中存在的诊断扩大化倾向、人格特征关系、心理创伤界定、创伤性事件与精神障碍的关系、精神损伤程度的评定以及鉴别诊断进行分析论证。结果应激源的强烈程度并非导致PTSD发生的唯一因素,患者在创伤性事件前的人格特征、幼年经历、生活处境、遗传易感性以及事件后的社会支持系统启动程度等均可成为PTSD潜在致病因素。结论PTSD司法精神病学鉴定应采取多元化诊查措施做出评定,谨慎处置伪现象干扰。     

全外显子组测序技术探寻家族性颅内动脉瘤致病基因的研究进展

家族性颅内动脉瘤的病因及发病机制仍不明确,其流行病学及遗传学特点表明遗传因素在其发病机制中发挥重要作用。全外显子组测序技术可用于家族性颅内动脉瘤的遗传学研究,并定位一些新的致病基因,本文将对其进行综述。     

多发性硬化的遗传研究进展

多发性硬化(MS)是一种遗传因素和环境因素共同作用,导致自身免疫反应性炎症损伤的疾病。研究资料表明 MS具有遗传异质性,其遗传易感性是由多个微效基因共同决定。通过关联分析发现了很多 MS 易患位点,其中 MHC 与多发性硬化密切相关,某些易患基因之间可能存在相互作用。利用遗传标记进行基因组扫描为 MS 遗传研究提供了更加全面的信息。目前有关 MS 遗传学分析方法主要有病例对照研究、TDT、共享等位基因分析法和遗传连锁分析。     

烟雾病遗传学研究

烟雾病是一种慢性进行性、闭塞性脑血管病,其病因和发病机制目前尚未阐明。近年来国内外大量研究证实其存在遗传易感性,且遗传性因素在发病机制中的作用较获得性因素更加重要。本文就近年来烟雾病遗传学研究进展进行综述,以为早期诊断和有效精准治疗提供指导。     

重症肌无力遗传易感基因的研究进展

重症肌无力发病机制尚不明确,随着分子生物学技术的发展,其发病机制在分子水平上获得阐述,本文从HLA等位基因、乙酰胆碱受体亚基基因、免疫球蛋白重链基因、T淋巴细胞受体基因对重症肌无力的遗传易感性进行了综述。     

The genetic background to PTSD

Although extensive research has already been done on the genetic bases of psychiatric disorders, little is known about polygenetic influences in posttraumatic stress disorder (PTSD). This article reviews molecular genetic studies relating to PTSD that were found in a literature search in Medline, Embase and Web of Science. Association studies have investigated 8 major genotypes in connection with PTSD. They have tested hypotheses involving key candidate genes in the serotonin (5-HTT), dopamine (DRD2, DAT), glucocorticoid (GR), GABA (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). The studies have produced inconsistent results, many of which may be attributable to methodological shortcomings and insufficient statistical power. The complex aetiology of PTSD, for which experiencing a traumatic event forms a necessary condition, makes it difficult to identify specific genes that substantially contribute to the disorder. Gene-finding strategies are difficult to apply. Interactions between different genes and between them and the environment probably make certain people vulnerable to developing PTSD. Gene-environmental studies are needed that focus more narrowly on specific, distinct endophenotypes and on influences from environmental factors.     

An overview of posttraumatic stress disorder genetic studies by analyzing and integrating genetic data into genetic database PTSDgene

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric syndrome with complex etiology. Studies aiming to explore genetic susceptibility and environmental triggers of PTSD have been increasing. However, the results are limited and highly heterogeneous. To understand the genetic study status of PTSD and explore more reliable candidates, we obtained 105 PTSD related genetic studies by comprehensively literature searching and filtering 1762 studies. Detailed phenotype and sample information for each study and association results for each genetic marker were extracted. Based on the extracted data, we reviewed the PTSD genetic research status and further conducted bioinformatics analyses for the genetic data. Our analyses summarized the landscape of PTSD genetic studies, identified the genes with most genetic evidence, discovered the biological function of the candidate variants/genes and enlarged the overall candidates for future investigations. All the data were stored in the PTSDgene database (http://ptsdgene.psych.ac.cn). We hope PTSDgene could be a platform for the rapid growth of PTSD genetic data and provide new insights into the pathogenesis of PTSD.     

Gene-environment interaction in posttraumatic stress disorder

The purpose of this article is to encourage research investigating the role of measured gene-environment interaction (G × E) in the etiology of posttraumatic stress disorder (PTSD). PTSD is uniquely suited to the study of G × E as the diagnosis requires exposure to a potentially-traumatic life event. PTSD is also moderately heritable; however, the role of genetic factors in PTSD etiology has been largely neglected both by trauma researchers and psychiatric geneticists. First, we summarize evidence for genetic influences on PTSD from family, twin, and molecular genetic studies. Second, we discuss the key challenges in G × E studies of PTSD and offer practical strategies for addressing these challenges and for discovering replicable G × E for PTSD. Finally, we propose some promising new directions for PTSD G × E research. We suggest that G × E research in PTSD is essential to understanding vulnerability and resilience following exposure to a traumatic event. Dr. Koenen is supported in part by US-NIMH K08 MH070627. Ananda Amstadter is supported by US-NIAAA T32 AA007474. Nicole Nugent is supported by US-NIMH T32 MH18869.     

Robust Findings From 25 Years of PTSD Genetics Research

Purpose of Review

The purpose of this review is to contextualize findings from the first 25 years of PTSD genetics research, focusing on the most robust findings and interpreting results in light of principles that have emerged from modern genetics studies.

Recent Findings

Genome-wide association studies (GWAS) encompassing tens of thousands of participants enabled the first molecular genetic heritability and genetic correlation estimates for PTSD in 2017. In 2018, highly promising loci for PTSD were reported, including variants in and near the CAMKV, KANSL1, and TCF4 genes.

Summary

Twin studies from 25 years ago established that PTSD is genetically influenced and foreshadowed the molecular genetic findings of today. Discoveries that were impossible with smaller studies have been achieved via collaborative/team-science efforts. Most promisingly, individual genomic loci offer entirely novel clues about PTSD etiology, providing the raw material for transformative discoveries, and the future of PTSD research is bright.

     

Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies

Post-traumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder that constitutes a major health care burden. Despite evidence supporting a genetic predisposition to PTSD, the precise genetic loci remain unclear. Herein we review the current state and limitations of genetic research on PTSD. Although recent years have seen an exponential increase in the number of studies examining the influence of candidate genes on PTSD diagnosis and symptomatology, most studies have been characterized by relatively low rates of PTSD, with apparent inconsistencies in gene associations linked to marked differences in methodology. We further discuss how current advances in the genetics field can be applied to studies of PTSD, emphasizing the need to adapt a genome-wide approach that facilitates discovery rather than hypothesis testing. Genome-wide association studies offer the best opportunity to identify novel “true” risk variants for the disorder that in turn has the potential to inform our understanding of PTSD etiology.     

Previous exposure to trauma and PTSD effects of subsequent trauma: results from the Detroit Area Survey of Trauma.

OBJECTIVE: With the exception of a few reports of higher rates of childhood trauma in Vietnam veterans with posttraumatic stress disorder (PTSD), little is known about the influence of previous exposure to trauma on the PTSD effects of subsequent trauma. The authors examine interrelated questions about the effects of previous exposure to trauma. METHOD: A representative sample of 2,181 individuals in southeast Michigan were interviewed by telephone to record lifetime history of traumatic events specified in DSM-IV as potentially leading to PTSD. PTSD was assessed with respect to a randomly selected index trauma from the list of events reported by each respondent. RESULTS: History of any previous exposure to traumatic events was associated with a greater risk of PTSD from the index trauma. Multiple previous events had a stronger effect than a single previous event. The effect of previous assaultive violence persisted over time with little change. When they examined several features of the previous exposure to trauma, the authors found that subjects who experienced multiple events involving assaultive violence in childhood were more likely to experience PTSD from trauma in adulthood. Furthermore, previous events involving assaultive violence--single or multiple, in childhood or later on--were associated with a higher risk of PTSD in adulthood. CONCLUSIONS: Previous exposure to trauma signals a greater risk of PTSD from subsequent trauma. Although these results are consistent with a sensitization hypothesis, like the results from previous research on PTSD, they do not address the mechanism of increased responsivity to trauma. Long-term observational studies can further elucidate these observations.     

EARLY INTERVENTIONS FOR PTSD: A REVIEW

The high prevalence of trauma exposure and subsequent negative consequences for both survivors and society as a whole emphasize the need for secondary prevention of posttraumatic stress disorder. However, clinicians and relief workers remain limited in their ability to intervene effectively in the aftermath of trauma and alleviate traumatic stress reactions that can lead to chronic PTSD. The scientific literature on early intervention for PTSD is reviewed, including early studies on psychological debriefing, pharmacological, and psychosocial interventions aimed at preventing chronic PTSD. Studies on fear extinction and memory consolidation are discussed in relation to PTSD prevention and the potential importance of immediate versus delayed intervention approaches and genetic predictors are briefly reviewed. Preliminary results from a modified prolonged exposure intervention applied within hours of trauma exposure in an emergency room setting are discussed, along with considerations related to intervention reach and overall population impact. Suggestions for future research are included. Prevention of PTSD, although currently not yet a reality, remains an exciting and hopeful possibility with current research approaches translating work from the laboratory to the clinic.     

Psychopharmacological treatment in PTSD: a critical review

Introduction: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder that is heterogeneous in its nature, and often presents with other psychiatric comorbidities. As a result, empirical research on effective pharmacotherapy for PTSD has produced complex findings. This article reviews the existing research literature on pharmacological treatments for PTSD, identifies the most effective treatments, and where possible examines their mechanism of action with respect to the neurobiology of PTSD. Methods: We examined reports of clinical trials of psychotropic agents carried out with PTSD patients and published in peer-reviewed journals, as well as reports from presentations at scientific meetings between 1966 and 2001. Results: Numerous medications are effective in treating PTSD. These include tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin reuptake inhibitors. Considering reported overall efficacy and side effects profiles, selective serotonin reuptake inhibitors emerge as the preferred first line treatment for PTSD. Mood stabilizers, atypical neuroleptics, adrenergic agents, and newer antidepressants also show promise, but require further controlled trials to clarify their place in the pharmacopoeia for PTSD. Discussion: There is clear evidence for effective pharmacotherapy of PTSD. Future improvements in the treatment of this disorder await further clinical trials and neurobiological research.     

Protocol for investigating genetic determinants of posttraumatic stress disorder in women from the Nurses' Health Study II

Background

One in nine American women will meet criteria for the diagnosis of posttraumatic stress disorder (PTSD) in their lifetime. Although twin studies suggest genetic influences account for substantial variance in PTSD risk, little progress has been made in identifying variants in specific genes that influence liability to this common, debilitating disorder.

Methods and design

We are using the unique resource of the Nurses Health Study II, a prospective epidemiologic cohort of 68,518 women, to conduct what promises to be the largest candidate gene association study of PTSD to date. The entire cohort will be screened for trauma exposure and PTSD; 3,000 women will be selected for PTSD diagnostic interviews based on the screening data. Our nested case-control study will genotype1000 women who developed PTSD following a history of trauma exposure; 1000 controls will be selected from women who experienced similar traumas but did not develop PTSD. The primary aim of this study is to detect genetic variants that predict the development of PTSD following trauma. We posit inherited vulnerability to PTSD is mediated by genetic variation in three specific neurobiological systems whose alterations are implicated in PTSD etiology: the hypothalamic-pituitary-adrenal axis, the locus coeruleus/noradrenergic system, and the limbic-frontal neuro-circuitry of fear. The secondary, exploratory aim of this study is to dissect genetic influences on PTSD in the broader genetic and environmental context for the candidate genes that show significant association with PTSD in detection analyses. This will involve: conducting conditional tests to identify the causal genetic variant among multiple correlated signals; testing whether the effect of PTSD genetic risk variants is moderated by age of first trauma, trauma type, and trauma severity; and exploring gene-gene interactions using a novel gene-based statistical approach.

Discussion

Identification of liability genes for PTSD would represent a major advance in understanding the pathophysiology of the disorder. Such understanding could advance the development of new pharmacological agents for PTSD treatment and prevention. Moreover, the addition of PTSD assessment data will make the NHSII cohort an unparalleled resource for future genetic studies of PTSD as well as provide the unique opportunity for the prospective examination of PTSD-disease associations.     

Differential etiology of posttraumatic stress disorder with conduct disorder and major depression in male veterans.

BACKGROUND: Epidemiologic studies reveal that posttraumatic stress disorder (PTSD) is highly comorbid with both conduct disorder and major depression in men. The genetic and environmental etiology of this comorbidity has not been examined. METHODS: Data were analyzed from 6744 middle-aged male-male monozygotic and dizygotic twins from the Vietnam Era Twin Registry. Conduct disorder, major depression, and PTSD were assessed via telephone interview using the Diagnostic Interview Schedule for the DSM-III-R in 1992. Structural equation modeling was used to estimate additive genetic, shared environmental, and individual-specific environmental effects common and specific to conduct disorder, major depression, and PTSD. RESULTS: The association between conduct disorder and PTSD was explained primarily by common shared environmental influences; these explained 10% (95% confidence interval: 6%-17%) of the variance in PTSD. The association between major depression and PTSD was largely explained by common genetic influences; these explained 19% (95% confidence interval: 11%-26%) of the variance in PTSD. CONCLUSIONS: Our findings suggest that different etiologic mechanisms explain the association of conduct disorder and major depression with PTSD in male veterans. If replicated in other populations, results suggest research aimed at identifying specific genetic and environmental factors that influence PTSD may benefit from starting with those that have been more consistently and strongly associated with major depression and conduct disorder.