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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遗传性疾病，在世界人口中的终生患病率约为2%。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。遗传方式还不完全清楚，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的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地点之一，其部分结果最近在下面提到的小组出版物以及我们以前的年度报告中报道。此外，一系列的关联研究，已确定和评估几个基因在强迫症和相关疾病正在继续。在我们实验室的合作研究中，我们还致力于澄清强迫症和相关疾病的基本表型特征，有时被称为“强迫症谱系障碍”，在过去几年发表的报告中。我们目前有一系列多方面的强迫症表型特征，这些特征跨越了传统的诊断名称（DSM-4和DSM-5）。一些可能导致强迫症但没有典型强迫症特征的亚障碍的例子包括我们最近和以前对图雷特氏症、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。双相情感障碍也是与双相遗传学协会继续合作调查的直接和分子遗传学研究的主题。正在进行的研究中的作用，5-羟色胺，SLC 6A 4基因和其他主要的5-羟色胺基因加上SLC 1A 1在强迫症和相关的疾病，如抽动秽语障碍（其中50%的患者符合诊断标准的强迫症）。去年发表了一篇关于发现与图雷特氏症相关的多种常见和罕见的SLC 6A 4变体的手稿，包括5 HTTLPR、rs 25531、rs 25532和SERT I425 V变体（莫亚等人，2013年）。SLC 6A 4变体与人类中不同SRI治疗反应的关系代表了基于基因对多巴胺能药理学反应的影响的另一个例证，即，一个新的SERT为基础的药物基因组学，直接相关的治疗人类神经精神疾病，如强迫症和抑郁症，以及其他与降钙素相关的人类疾病，我们最近审查。最近的治疗和遗传研究证据表明，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，神经元谷氨酸转运蛋白是谷氨酸可用性的主要调节剂。这种谷氨酸转运蛋白EAAT 3由位于染色体区域9 p24内的基因SLC 1A 1编码。9 p24基因连锁分析和候选基因研究表明，SLC 1A 1可能参与了强迫症的发展。我们对SLC 1A 1的大型病例对照研究包括我们实验室收集的500多名OCD先证者和对照者。此外，最近对SLC 1A 1表达和数据进行了评估，以进一步了解SLC 1A 1的功能。我们目前正在继续进一步的实验室研究，这种基因使用转基因技术在小鼠中。莫亚博士，以前从我们的实验室，创造了条件Slc 1a 1小鼠，其中一组有这个基因删除和另一组优先在前脑过表达这个基因。创造这两种相反功能的Slc 1a 1小鼠的理由是基于人类SLC 1A 1研究的结果，关于该基因在强迫症中是否功能低下或功能亢进。这些研究表明，SLC 1A 1和SLC 6A 4一样，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和有用的补充模型方法，以加强未来的GWAS和候选罕见功能基因在神经精神和其他疾病，这代表了一个巨大的公共卫生负担的研究。事实上，包括强迫症在内的七种神经精神疾病在世界卫生组织的一份报告中被列为成年人长期残疾的主要原因。因此，预计这些研究将对公共卫生产生相当大的影响。值得注意的是，我们的小组继续与强迫症协作遗传学研究（OCGAS）和强迫症基金会（OCF）小组的合作者以及其他校内和校外个人合作者分享我们25年以上收集的DNA和表型数据，从而加强了对强迫症和相关疾病的潜在贡献的全球搜索，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协作GWAS的构想是为了补充早期基于OCGS家族的基因组连锁研究，该研究包括299对受OCD影响的兄弟姐妹和其他家庭成员，现在包括1100多个个体。迄今为止，OCGS的研究产生了20多篇出版物，最近的两篇是去年。引用我们的科学报告的其他论文的引用数量现在超过35，000。本年度报告的方案编号为96-M-0124，NCT编号为NCT 00001548。

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？