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

• 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
• 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

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遗传性疾病，世界人口的终生患病率约为百分之二。一级家庭成员和强迫症先证者患强迫症和相关疾病的风险高出十倍。遗传模式尚不完全清楚，但可能很复杂，涉及多个小到中等影响的遗传位点。我们的实验室在强迫症及其遗传学研究中发挥了主导作用超过 25 年，并且是多中心、全基因组强迫症研究项目的创始单位之一，该项目的部分结果最近已在下面以及我们之前的年度报告中提到的该集团的出版物。此外，一系列已识别和评估强迫症及相关疾病中的多个基因的关联研究仍在继续。 在我们实验室的合作研究中，我们还致力于在过去几年发表的报告中阐明强迫症和相关疾病（有时被称为“强迫症谱系障碍”）的基本表型特征。目前，我们拥有一系列跨越传统诊断名称（DSM-IV 和 DSM-5）的强迫性表型特征。一些可能导致强迫症但没有典型强迫症特征的亚疾病的例子包括我们最近和之前对图雷特氏症、多动症、头部创伤和囤积症以及共病情感障碍（包括双相情感障碍）的研究。双相情感障碍也是双相情感障碍遗传学联盟小组持续合作研究中直接和分子遗传学研究的主题。 血清素、SLC6A4 基因和其他主要血清素基因加上 SLC1A1 在强迫症和抽动秽语症等相关疾病（其中 50% 的患者符合强迫症的诊断标准）中的作用的研究正在进行中。去年发表了一份手稿，介绍了与抽动秽语症相关的多种常见和罕见 SLC6A4 变体，包括 5HTTLPR、rs25531、rs25532 和 SERT I425V 变体（Moya 等人，2013）。 SLC6A4 变体与人类不同 SRI 治疗反应的关系进一步说明了基于基因对血清素能药理反应的影响，即一种新的基于 SERT 的药物基因组学，与人类神经精神疾病（如强迫症和抑郁症）的治疗直接相关。以及其他与血清素相关的人类疾病，正如我们最近回顾的那样。 最近的治疗和遗传学研究证据表明，另一种神经递质系统可能导致强迫症。与血清素系统中的 SERT 一样，神经元谷氨酸转运蛋白是谷氨酸可用性的主要调节因子。这种谷氨酸转运蛋白 EAAT3 由位于染色体区域 9p24 内的基因 SLC1A1 编码。最近来自 9p24 基因连锁分析和候选基因研究的证据表明 SLC1A1 可能参与强迫症的发展。 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 多名强迫症先证者和对照。此外，最近评估了 SLC1A1 表达和数据，以进一步了解 SLC1A1 功能。我们目前正在利用转基因技术在小鼠中继续对该基因进行进一步的实验室研究。我们实验室的 Moya 博士创造了条件性 Slc1a1 小鼠，其中一组删除了该基因，另一组优先在前脑过度表达该基因。创造这两只功能相反的 SLC1A1 小鼠的理由是基于人类 SLC1A1 研究的结果，即该基因在强迫症中是否功能低下或功能亢进。这些研究综合起来表明，SLC1A1 与 SLC6A4 一样，是强迫症的易感基因。我们使用的表达和数据库挖掘方法提供了新的、有用的补充模型方法，以加强未来的 GWAS 和神经精神疾病和其他疾病的候选稀有功能基因研究，这些疾病代表了巨大的公共卫生负担。事实上，世界卫生组织的一份报告将包括强迫症在内的七种神经精神疾病列为导致成年人长期残疾的主要原因之一。因此，这些研究预计将对公共健康产生相当大的影响。 值得注意的是，我们小组继续与强迫症协作遗传学研究 (OCGAS) 和强迫症基金会 (OCF) 小组以及其他校内小组的合作者分享我们 25 多年收集的 DNA 和表型数据和校外个人合作者，从而加强全球对强迫症和相关疾病的根本原因的研究，这些疾病是主要的公共卫生问题。下面列出的去年发表的许多论文都是这些合作研究的结果。 OCF 合作 GWAS 旨在补充早期基于 OCGS 家庭的基因组连锁研究，该研究涉及 299 对受强迫症影响的兄弟姐妹以及其他家庭成员，现在已超过 1100 人。迄今为止，OCGS 研究已发表 20 多篇出版物，最近的两篇于去年发表。 目前引用我们科学报告的其他论文的引用次数已超过 35,000 次。 本年度报告的协议号为 96-M-0124，NCT 号为 NCT00001548。

项目成果

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
• 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
• 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？

• DOI: 10.1021/cn3002224
• 发表时间: 2013
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Murphy,DennisL;Maile,MichelleS;Vogt,NicholasM
• 通讯作者: Vogt,NicholasM

Separation anxiety disorder in OCD.

强迫症中的分离焦虑症。

• DOI: 10.1002/da.20773
• 发表时间: 2011
• 期刊: Depression and anxiety
• 影响因子: 7.4
• 作者: Mroczkowski,MeganM;Goes,FernandoS;Riddle,MarkA;Grados,MarcoA;Bienvenu3rd,OJoseph;Greenberg,BenjaminD;Fyer,AbbyJ;McCracken,JamesT;Rauch,ScottL;Murphy,DennisL;Knowles,JamesA;Piacentini,John;Cullen,Bernadette;Rasmussen,
• 通讯作者: Rasmussen,