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

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. 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 2012-2013. We currently have a multifaceted array of compulsive phenotypical features that cut across traditional diagnostic designations (DSM-IV and DSM-5). In continuing efforts, our group and our collaborators have been using latent class modeling to go beyond factor and cluster analyses in order to parse OCD and related disorders by considering underlying features and comorbid disorders (e.g., affective/bipolar disorders) and life stresses. 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 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 this 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 diseases 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, EAAC3, 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 950 OCD probands and controls collected by our Lab were published this year. In addition, SLC1A1 expression and data were recently evaluated to gain further insights into SLC1A1 function. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice and Dr. Moya 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 the equivocal 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 provides a new and useful complementary model approach 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 the 2001 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. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. These studies thus bring an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Also 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 (OCGS) 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 collaborative study to which our Lab contributed DNA and phenotype data based at Massachusetts General Hospital yielded a case-control genome association study involving 7022 individuals published in 2012. One of the top signals obtained was in DLGAP1, coding a post-synaptic density (PSD) protein with high similarity to another PSD gene, DLGAP3 (SAPAP3) which we found to have rare variants enriched in OCD patients versus controls, as reported in a 2011 paper from our group and colleagues. 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 20 publications to date, the most recent last year. This study conducted fine mapping followed by SNP association studies of two regions identified in the initial linkage analysis. Associations were identified in or near a set of associated homeobox genes including MEIS2. Two of these form a heterodemeric complex. All three are involved in neurodevelopment and the heterodemeric complex is specifically known to affect development of the striatum, a brain region previously implicated in OCD via human brain imaging studies. Citations numbers of other papers that have referenced our scientific reports number over 35,000 as of August, 2013. 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,最近在该研究中报告了部分结果。集团的出版物下面指出。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谱系障碍”,该报告在2012 - 2013年发布的报告中。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)。在不断的努力中,我们的小组和我们的合作者一直在使用潜在的类建模超越因素和聚类分析,以通过考虑潜在的特征和合并症(例如情感/双相情感障碍)和生活压力来解析OCD和相关疾病。可以在没有经典的强迫症功能的情况下可以找到一些可导致强迫症的某些子订单的例子,包括我们最近和先前对Tourette的疾病和ho积和合并症情感障碍(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)。今年出版了一份手稿,内容涉及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变体与人类中不同SRI治疗反应的关系代表了基于基因的影响血清素能药理学反应的影响,即与人类神经精神疾病(如OCD和OCD和OCD和OCD和OCD和OCD和OCD和OCD和抑郁症)的治疗直接相关的新型基于SERT的药物基因组学以及我们最近所回顾的其他与5-羟色胺相关的人类疾病。 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EAAC3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今年发表了总共950多种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。我们发现SLC1A1的基因表达在人类细胞系中是可遗传的。我们确定了与基因表达水平相关的SLC1A1或附近的三个SNP。此外,这些SNP中的两个还预测了人类后脑组织中的表达水平,发现一个SNP在报告基因研究中具有功能后果。目前,我们正在使用小鼠中的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,而我们实验室的Moya博士创建了有条件的SLC1A1小鼠,其中一组已删除该基因,而另一种集合则优先超过该基因。创建这两只相反功能性SLC1A1小鼠的合理是基于人类SLC1A1研究的模棱两可的发现,该研究是关于该基因在强迫症中可能是功能性功能低下还是功能过度功能。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一种新的和有用的补充模型方法,可以增强未来的GWAS和候选稀有功能基因研究,这些神经精神病学和其他疾病代表了巨大的公共卫生负担。实际上,2001年世界卫生组织报告中列出了包括OCD在内的七种神经精神疾病,是成年人多年延长残疾的主要原因之一。 因此,预计这些研究将产生相当大的公共卫生影响。 在OCD遗传学的其他研究中,我们基于某些与强迫症相关的强迫性行为的动物模型专注于OCD的候选基因。因此,这些研究使可能与特定单基因更紧密相关的OCD亚型或亚种群更加尖锐。 还值得注意的是,我们的小组继续与强迫症合作遗传学研究(OCGS)和强迫症基础(OCF)以及其他人以及其他组中以及其他人以及其他组中以及其他人以及其他组合以及其他人以及其他人以及其他人以及其他组中的合作者共享25年以上的DNA和表型数据。壁内和壁外个体合作者,从而增强了全球对强迫症和相关疾病的基本贡献的搜索,这是主要的公共卫生问题。去年发表的许多论文均由这些协作研究产生。 我们的实验室在马萨诸塞州综合医院贡献DNA和表型数据的合作研究产生了一项病例对照基因组协会研究,涉及2012年发表的7022个个体。获得的主要信号之一是DLGAP1,编码后突触后密度(PSD) )与另一个PSD基因DLGAP3(SAPAP3)相似的蛋白质,我们发现它具有富含强迫症患者与对照组的稀有变体,这是我们小组和同事的2011年论文中报道的。 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的研究迄今为止产生了20个出版物,这是去年的最新出版物。这项研究进行了精细的映射,然后对初始连锁分析中确定的两个区域进行了SNP关联研究。在包括MEIS2在内的一系列相关的同源基因基因中发现了关联。其中两个形成了异构体复合物。这三个都参与了神经发育,异构络合物均特异性地影响纹状体的发展,纹状体的发展是以前通过人脑成像研究与OCD有关的大脑区域。 截至2013年8月,引用了我们的科学报告数量超过35,000的其他论文数量。 该年度报告的协议号为96-m-0124,NCT号为NCT0000001548。

项目成果

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DENNIS L MURPHY其他文献

DENNIS L MURPHY的其他文献

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{{ truncateString('DENNIS L MURPHY', 18)}}的其他基金

Bipolar Disorder Genetics: An Affected Sib Pair Family S
双相情感障碍遗传学:受影响的同胞对家庭 S
  • 批准号:
    6546827
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
BIPOLAR DISORDERS GENETICS: AN AFFECTED SIB PAIR FAMILY
双相情感障碍遗传学:受影响的同胞兄弟姐妹家庭
  • 批准号:
    6435036
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
Bipolar Disorder Genetics: An Affected Sib Pair Family S
双相情感障碍遗传学:受影响的同胞对家庭 S
  • 批准号:
    6681068
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
The Genetics Of Obsessive Compulsive Disorder
强迫症的遗传学
  • 批准号:
    7304034
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
The Genetics Of Obsessive Compulsive Disorder
强迫症的遗传学
  • 批准号:
    7594484
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
Genetic Mouse Models for the Study of Serotonin, Dopamine and Glutamate Function and Behavior
用于研究血清素、多巴胺和谷氨酸功能和行为的基因小鼠模型
  • 批准号:
    8939930
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
ANIMAL MODELS FOR STUDY OF NEUROTRANSMITTER FUNCTION/NEUROPHARMACOLOGIC EFFECTS
用于研究神经递质功能/神经药理学作用的动物模型
  • 批准号:
    6432770
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
THE PSYCHOLBIOLOGY AND TREATMENT OF OBESSIVE COMPULSIVE DISORDER IN ADULTS
成人强迫症的心理生物学和治疗
  • 批准号:
    6432771
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
The Genetics Of Obsessive Compulsive Disorder In Adults
成人强迫症的遗传学
  • 批准号:
    6970030
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    $ 75.37万
  • 项目类别:

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单核细胞产生S100A8/A9放大中性粒细胞炎症反应调控成人Still病发病及病情演变的机制研究
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