The Genetics of Obsessive Compulsive Disorder and Related OCD Spectrum Disorders

强迫症和相关强迫症谱系障碍的遗传学

基本信息

批准号：
8939931
负责人：
DENNIS L MURPHY
金额：
$ 9.32万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8939931
关键词：
9p24 Adult Affect Animal Model Annual Reports Anxiety Attention deficit hyperactivity disorder Bipolar Disorder Brain Candidate Disease Gene Case-Control Studies Collection Complex Compulsive Hoarding Craniocerebral Trauma DNA DSM-IV Data Databases Development Diagnostic Diagnostic and Statistical Manual of Mental Disorders Disease EAAT3 Excitatory Amino Acid Antagonists Extramural Activities Family Family member Foundations Future Genes Genetic Genome Gilles de la Tourette syndrome Glutamate Transporter Glutamates Glutathione Goals Human Individual Investigation Laboratories Manuscripts Medical Mental Depression Mining Modeling Molecular Genetics Monobactams Mood Disorders Mus Neurons Neurotransmitters Obsessive compulsive behavior Obsessive-Compulsive Disorder Paper Pathway interactions Patients Pharmacogenomics Phenotype Play Population Prevalence Prosencephalon Proteins Protocols documentation Public Health Publications Publishing Reporting Riluzole Role Series Serotonin Siblings Site Susceptibility Gene Synapses System Techniques Transgenic Organisms Variant Work World Health Organization base disability extracellular gene environment interaction genetic linkage analysis genetic variant genome wide association study genome-wide high risk insight knowledge base meetings neuropsychiatry neurotropic overexpression proband response treatment response

项目摘要

OCD is a severe, heritable condition with a lifetime prevalence of about two percent in world populations. First-degree family members and OCD probands are at a ten-fold higher risk of developing OCD and related disorders. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our Laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center, genome-wide project for studies of OCD, partial results of which have recently been reported in the group's publications noted below as well as in our previous annual reports. In addition, a series of association studies that has identified and evaluated several genes in OCD and related disorders is continuing. In our Lab's collaborative investigations, we have also worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in reports published in the last several years. We currently have a multifaceted array of compulsive phenotypical features that cut across traditional diagnostic designations (DSM-IV and DSM-5). Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of Tourette's disorder, ADHD, head trauma and hoarding as well as of comorbid affective disorders, including bipolar disorder. Bipolar disorder is also the subject of direct and molecular genetic studies in continuing collaborative investigations with the Bipolar Genetics Consortium group. Studies are ongoing of the role of serotonin, the SLC6A4 gene and other major serotonin genes plus SLC1A1 in OCD and related disorders such as Tourette disorder (in which 50% of patients meet diagnostic criteria for OCD). A manuscript was published last year about the multiple common and rare SLC6A4 variants found to be associated with Tourette's Disorder including the 5HTTLPR, rs25531, rs25532 and SERT I425V variants (Moya et al., 2013). The relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human disorders, as we have recently reviewed. Recent evidence from treatment and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter, EAAT3, is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies has suggested probable involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included a total of over 500 OCD probands and controls collected by our Lab. In addition, SLC1A1 expression and data were recently evaluated to gain further insights into SLC1A1 function. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice. Dr. Moya, formerly from our Lab, has created conditional Slc1a1 mice, one set of which has this gene deleted and another set which preferentially overexpresses this gene in the forebrain. The rational for creating these two opposite functional Slc1a1 mice was based on l findings from the human SLC1A1 studies regarding whether this gene might be hypofunctional or hyperfunctional in OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provide new and useful complementary model approaches to strengthen future GWAS and candidate rare functional gene studies in neuropsychiatric and other disorders, which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in a World Health Organizations report as among the leading causes of years of extended disability among adults. Thus these studies are expected to have a considerable public health impact. Of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGAS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Many papers that were published in the last year that are listed below resulted from these collaborative studies. The OCF collaborational GWAS was conceived to compliment the earlier OCGS family-based genome linkage study of 299 OCD-affected sibling pairs together with other family members and now constitutes more than 1100 individuals. The OCGS studies generated more than 20 publications to date, the most recent two last year. Citations numbers of other papers that have referenced our scientific reports now number over 35,000. The protocol number for this Annual Report is 96-M-0124 and the NCT number is NCT00001548.

强迫症是一种严重的，可遗传的状况，世界人口的终生患病率约为2％。一级家庭成员和强迫症概率的患病风险和相关疾病的风险高十倍。遗传模式尚不完全理解，但可能很复杂，涉及多个遗传基因座的小至中等效应。我们的实验室在OCD及其遗传学的研究中发挥了领先作用，已有25年以上，并且是多中心，全基因组研究的OCD研究的创始场所之一，该项目的一部分结果最近在以下小组的出版物中报告了，以及我们先前的年度报告。此外，一系列的关联研究已经确定并评估了OCD和相关疾病中的几个基因。在我们实验室的合作调查中，我们还努力阐明OCD和相关疾病的基本表型特征，有时是指定为“ OCD Spectrum障碍”，在过去几年中发表的报告中。目前，我们有一系列强迫性表型特征，这些特征跨越了传统的诊断名称（DSM-IV和DSM-5）。可以在没有经典强迫症特征的情况下可以找到一些可导致强迫症的某些子调节的示例，包括我们最近和先前对Tourette疾病，ADHD，头部创伤和ho积以及合并症情感障碍（包括躁郁症）的研究。双相情感障碍也是与双极遗传联盟组进行持续合作研究的直接和分子遗传研究的主题。研究正在进行有关5-羟色胺，SLC6A4基因和其他主要5-羟色胺基因以及SLC1A1在OCD和相关疾病中的作用（其中50％的患者符合OCD诊断标准）。去年发表了一份手稿，内容涉及发现与图雷特障碍有关的多种常见和稀有的SLC6A4变体，包括5HTTLPR，RS25531，RS25532和SERT I425V变体（Moya等，2013）。 SLC6A4变体与人类不同SRI治疗反应的关系代表了基于基因的影响对血清素能药理学反应的影响，即基于SERT的新药物基因组学直接与人类神经精神疾病的治疗直接相关，例如OCD和OCD和抑郁症，例如其他人类疾病，并与其他人类的疾病症相关。治疗和遗传研究的最新证据表明，另一种神经递质系统可能有助于强迫症。与5-羟色胺系统中的SERT一样，神经谷氨酸转运蛋白是谷氨酸可用性的主要调节剂。该谷氨酸转运蛋白EAAT3由位于9p24染色体区域内的基因SLC1A1编码。 9P24基因链接分析和候选基因研究的最新证据表明，SLC1A1可能参与了OCD的发展。我们对SLC1A1的大型病例对照研究包括我们实验室收集的总共500多个OCD检验和对照。此外，最近评估了SLC1A1表达和数据，以获得对SLC1A1函数的进一步见解。目前，我们正在使用小鼠中使用转基因技术继续对该基因进行进一步的基于实验室的研究。 Moya博士以前来自我们的实验室，已经创建了有条件的SLC1A1小鼠，其中一组已删除该基因，而另一组则优先表达该基因在前脑中。创建这两只相反功能的SLC1A1小鼠的合理是基于人类SLC1A1研究的L结果，即该基因在OCD中是否可能是功能性功能性或功能过度功能。这些研究一起，表明SLC1A1（如SLC6A4）是强迫症的敏感基因。我们使用的表达和数据库挖掘方法提供了新的且有用的补充模型方法，以增强神经精神病学和其他疾病中的未来GWAS和候选稀有功能基因研究，这代表了巨大的公共卫生负担。实际上，在世界卫生组织报告中将包括OCD在内的七种神经精神疾病列为成年人多年残疾多年的主要原因之一。因此，预计这些研究将产生相当大的公共卫生影响。值得注意的是，我们的小组继续与强迫症的强迫症协作遗传学研究（OCGAS）和强迫症基础（OCF）组（OCF）组（OCF）组中的合作者共享25年以上的DNA和表型数据集合，以及与其他校园合作者以及对全球公众的贡献进行了促进疾病的贡献，并与无关紧要的疾病相关的是，与其他相关的疾病相关的是，这是对OCD的贡献。去年发表的许多论文均由这些协作研究产生。 OCF协作GWA被认为是为了补充299个受OCD影响的兄弟姐妹对的基于OCG的家庭基因组链接研究，以及其他家庭成员，现在构成了1100多名个人。 OCGS研究迄今为止产生了20多个出版物，这是去年的最新出版物。现在引用了我们的科学报告的其他论文数量超过35,000。该年度报告的协议号为96-m-0124，NCT号为NCT0000001548。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder.

DOI：
10.1001/archgenpsychiatry.2009.6
发表时间：
2009-04
期刊：
ARCHIVES OF GENERAL PSYCHIATRY
影响因子：
0
作者：
Wendland, Jens R.;Moya, Pablo R.;Timpano, Kiara R.;Anavitarte, Adriana P.;Kruse, Matthew R.;Wheaton, Michael G.;Ren-Patterson, Renee F.;Murphy, Dennis L.
通讯作者：
Murphy, Dennis L.

Using individual items to clarify OCD symptom structure: the case for five factors.

使用单个项目来阐明强迫症症状结构：五个因素的案例。

DOI：
10.1176/appi.ajp.2009.09020287
发表时间：
2009
期刊：
The American journal of psychiatry
影响因子：
0
作者：
Pinto,Anthony;Greenberg,BenjaminD;Murphy,DennisL;Nestadt,Gerald;Rasmussen,StevenA
通讯作者：
Rasmussen,StevenA

Basal ganglia MR relaxometry in obsessive-compulsive disorder: T2 depends upon age of symptom onset.

DOI：
10.1007/s11682-009-9083-2
发表时间：
2010-03
期刊：
BRAIN IMAGING AND BEHAVIOR
影响因子：
3.2
作者：
Correia, Stephen;Hubbard, Emily;Hassenstab, Jason;Yip, Agustin;Vymazal, Josef;Herynek, Vit;Giedd, Jay;Murphy, Dennis L.;Greenberg, Benjamin D.
通讯作者：
Greenberg, Benjamin D.

5HTTLPR: White Knight or Dark Blight?

5HTTLPR：白骑士还是黑暗疫病？