The Genetics Of Obsessive Compulsive Disorder

强迫症的遗传学

• 批准号: 7594484
• 负责人: DENNIS L MURPHY
• 金额: $ 47.16万
• 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/7594484
• 关键词: 14p; 15q; 3q27; 6H,8H-3,4-dihydropyrimido(4,5-c)(1,2)oxazin-7-one; Adverse drug effect; Affect; Agoraphobia; Alcohol abuse; Alleles; Anxiety; Anxiety Disorders; Applications Grants; Area; Attention deficit hyperactivity disorder; Autistic Disorder; Behavior; Behavior Therapy; Bipolar Disorder; Brain; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 1; Clinical; Cluster Analysis; Cognitive Therapy; Comorbidity; Complex; Condition; Count; DNA; Data; Development; Dimensions; Disease; Disruption; Eating Disorders; Environment; Evaluation; Exhibits; Extramural Activities; Family; Fetal Development; Fibrinogen; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genome Scan; Genotype; Gilles de la Tourette syndrome; Goals; Grouping; Heterogeneity; Human; Individual; Investigation; Knowledge; Laboratories; Life; Literature; Maps; Medical; Mental Depression; Mental disorders; Methodology; Methods; Modeling; Mus; National Institute of Mental Health; Obsession; Obsessive-Compulsive Disorder; Panic Disorder; Pathway interactions; Patients; Pattern; Personality; Pharmaceutical Preparations; Phenotype; Placenta; Population; Prevalence; Prothrombin; Rate; Receptor Gene; Relative (related person); Religion and Spirituality; Reporting; Risk; Role; Sampling; Score; Series; Serotonin; Serotonin Syndrome; Severities; Signal Transduction; Significance Level; Site; Social Phobia; Statistical Methods; Symptoms; Synapses; System; TDO2 gene; Thinking; Thromboplastin; Trauma; Tryptophanase; Universities; Variant; base; case control; disorder subtype; early onset; follow-up; gene environment interaction; gene function; genetic association; genetic linkage analysis; genetic variant; genome wide association study; human WNT2 protein; improved; neuropsychiatry; neurotropic; novel; proband; research study; serotonin receptor; serotonin transporter; simulation; synaptic function; trait

Our particular disease focus has been OCD for the past two decades. However, because OCD, like other anxiety/depression disorders exhibits high comorbidity with multiple disorders, comorbidity of neuropsychiatric disorders itself has been an additional special focus in consideration of our gene e environment and gene x gene studies in humans and indirectly in murine models. Our studies of Sert-targeted mice (and those of our collaborators and colleagues) have continued to show many similarities between the multiple phenotypes of mice with disrupted Sert gene function and those of humans who possess at least five functional SERT variants. Obsessive-compulsive disorder (OCD) is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. The mode of inheritance is not well understood but is likely complex, involving multiple loci of small to moderate effect. Our laboratory has been active in studies of OCD and of its genetics for over 15 years, and in 2001 became one of the founding sites of a multi-center genetic study of OCD (P.I.: Dr. Gerald Nestadt of Johns Hopkins University). This study was approved via a competitive NIMH extramural grant application. Due to the accumulation of evidence supportive of genetic contributions to OCD, a series of association studies of candidate genes has been undertaken and reported in the literature, but only one, very small genome- wide scan of OCD had previously been reported. Our OCD genetic studies in the NIMH IRP contribute DNA and family evaluation data to this national multi-site, genome-wide study of OCD which described its methodology (Samuels et al., 2006) and reported the first results from a 10cM genome scan last year (Shugart et al., 2006). Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, the strongest evidence for linkage was found on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. The collaborative group is currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping genes involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods. In addition, within the NIMH-IRP, exploratory analyses of DNA, clinical personality and other features of 300 OCD probands plus 700 of their relatives with or without OCD-related disorders are being used to assess the candidacy status of gene variants and to better define the familial OCD phenotype. In one such study, factor and cluster analysis of 70 OCD symptoms rated in each of the 317 patients with OCD from our Lab revealed a four factor grouping of symptoms which showed specific relationships to comorbid psychiatric disorders. Thus, Factor I (aggressive, sexual, religious and somatic obsessions, and checking compulsions) was broadly associated with comorbid anxiety disorder and depression; Factor II (obsessions of symmetry, and repeating, counting and ordering/arranging compulsions) with bipolar disorders and panic disorder/agoraphobia; and Factor III (contamination obsessions and cleaning compulsions) with eating disorders. Factors I and II were associated with early onset OCD. The frequent co-occurrence of OCD with other psychiatric disorders and the relatively specific association patterns between OCD symptom dimensions and comorbid disorders support the importance of OCD subtyping for genetic, treatment, and other research studies of this heterogeneous disorder. In a gene-based follow-up to this study, an association was replicated between the SERT 5HTTLPR functional polymorphism and the symmetry/counting/ordering (Factor II) dimension of OCD symptoms. In further studies of the SERT gene in OCD and related disorders such as Tourettes syndrome, the 5HTTLPR together with a newly-discovered SNP (rs25531) within it were found to be associated with OCD in both a case-control and a family-based trios study. Improved methods to genotype these and other variants in OCD were reported. The OCGS selected a sub-phenotype, hoarding, for secondary evaluation across the genome, based upon prior data that hoarding behaviors represented an OCD dimension that was familial in this sib-pair sample (Hasler et al., 2006) and might represent a distinct sub-phenotype worthy of further investigation (Frost et al., 1996; Samuels et al., 2006; LaSalle-Ricci et al., 2006; Zhang et al., 2002; Wheaton et al., 2007). When the OCGS OCD sample was limited to those with hoarding obsessions and compulsions (38% of the total sample), a strong genome-wide signal was found at 14p, with a LOD of 2.9, which increased further when only those OCD probands with two or more relatives with hoarding were included (LOD = 3.7) (Samuels et al., 2007). The original 3q signal found in the entire OCD group disappeared in a hoarding subsample, but was enhanced in the remaining larger non-hoarding group. This suggests that some heterogeneity in other OCD genetic studies may be contributed to by individuals with hoarding features. Earlier studies by our group and by others examining the clinical features of individuals with OCD revealed greater OCD severity, greater prevalence of comorbid disorders including social phobia and bipolar disorder, different personality features and relative insensitivity to both drug and behavioral therapy among hoarders (Frost et al., 1996; Samuels et al., 2006; LaSalle-Ricci et al., 2006; Wheaton et al., 2007; Cromer et al., 2006) A fairly strong genetic association between SERT and OCD, autism, ADHD, alcohol abuse and bipolar disorder has been demonstrated (Murphy et al., 2004). However, as in almost all candidate gene studies, there are some discrepant results. These neuropsychiatric disorders are not thought to be the result of any one gene but are, rather, a genetically complex configuration of multiple genes in multiple systems interacting together. Evidence of the involvement of SERT variants in these disorders raises the distinct possibility that serotonin-related genes that cause alterations in function of the serotonin system (such as TPH2, AADC, MAOA/B, HTR1A) and other serotonin receptor genes, as well as FEV, LMX1b, ITG3, BDNF and others might also be contributing to the disorder. However, less is known at present about functional variants in these genes and they have been less comprehensively studied. Their exploration seems to be a necessary next step in considering serotonergic involvement in these and related disorders.

在过去的二十年中，我们的特殊疾病重点一直是强迫症。 但是，由于OCD像其他焦虑/抑郁症一样表现出高度合并症和多种疾病的合并症，因此，考虑到我们的基因环境和人类基因X基因研究，神经精神疾病本身的合并症本身一直是人类和鼠模型中的基因X基因研究的另一种特别重点。 我们对靶向SERT靶向小鼠（以及我们的合作者和同事的小鼠的研究）继续显示出具有破坏SERT基因功能的小鼠的多种表型与至少具有五个功能性SERT变体的人类的相似性。 强迫症（OCD）是一种严重的，可遗传的疾病，终生患病率约为世界人口。 继承方式尚未充分理解，但可能很复杂，涉及多个小到中等效应的基因座。我们的实验室一直积极研究强迫症及其遗传学的研究，已有15年以上，并于2001年成为OCD多中心遗传研究的创始场所之一（P.I。：Johns Hopkins University的Gerald Nestadt博士）。这项研究通过竞争性的NIMH外授予赠款申请批准。 由于积累了支持OCD遗传贡献的证据，在文献中已经进行了一系列候选基因的关联研究，但以前只有一个非常小的OCD基因组扫描。我们在NIMH IRP中的强迫症遗传研究为这项全国多站点，全基因组的OCD研究贡献了DNA和家庭评估数据，该研究描述了其方法（Samuels等，2006），并报道了上一次10cm基因组扫描的首次结果年（Shugart等，2006）。 通过对染色体3Q27-28（p = 0.0003），6q（p = 0.003），7p（p = 0.001），1q（p = 0.003）和15q（p = 0.006）的多点分析（p = 0.003），7p（p = 0.001），揭示了暗示性的连锁信号。使用“广泛”的OCD定义，在3Q27-28染色体上找到了最有力的连锁证据。 D3S1262和D3S2398的最高总体和Cox Lodall评分（2.67）分别发生在D3S1262和D3S2398上，这两个信号的基于仿真的p值分别为0.0003和0.0004，尽管对于这两个信号，基于模拟的基于基于仿真的基因组显着性水平均为0.0555555555555555555555555555555555。 。协变量分析表明，基因对1染色体的可能作用在增加早期发作形式的强迫症的风险中。 该协作集团目前正在五个区域进行精细的映射，并特别关注3Q27-28。鉴于OCD中可能的病因异质性，可以通过复制研究，基于家庭的大规模连锁研究以及新型统计方法的应用来增强参与该疾病的映射基因。 此外，在NIMH-IRP中，使用或没有强迫症相关的疾病的NIMH-IRP，对DNA，临床人格和其他300个OCD概率的其他特征的探索性分析，以及700个亲戚，以评估基因变异的候选状态并更好地定义基因的候选状态家族性强迫症表型。 在一项此类研究中，对我们实验室的317例强迫症患者中的每名患者的70例OCD症状的因子和聚类分析显示，症状的四个因素分组，这些因素与合并症的精神疾病有特定关系。 因此，I因素（积极，性，宗教和躯体痴迷以及对强迫的检查）与合并症焦虑症和抑郁症广泛有关。因子II（对称性的痴迷，重复，计数和顺序/安排强迫）对双相情感障碍和恐慌症/恐惧症；和因子III（污染的痴迷和清洁强迫）对饮食失调。 I和II的因素与早期OCD有关。强迫症与其他精神疾病的频繁同时出现以及强迫症症状维度和合并症之间的相对特定的关联模式支持OCD亚型对这种异质疾病的遗传，治疗和其他研究的重要性。 在这项研究的基于基因的随访中，在SERT 5HTTLPR功能多态性与对称/计数/顺序（因子II）OCD症状的维度之间复制了关联。 在进一步研究强迫症和相关疾病（例如Tourettes综合征）中的SERT基因时，发现5HTTLPR以及新发现的SNP（rs25531）在其中发现与Case-Control和基于家庭的Trios中的OCD有关学习。 报告了OCD中这些和其他变体的基因型的改进方法。 OCGS选择了基因组的二次评估的亚表型，基于先前的数据，即ho积行为代表了该同胞样本中家族性的OCD维度（Hasler等，2006），并可能代表一个独特的OCD维度。值得进一步研究的子表型（Frost等，1996; Samuels等，2006; Lasalle-Icci等，2006; Zhang等，2002; Wheaton等，2007）。 当OCGS OCD样品仅限于ho积的痴迷和强迫症（占总样本的38％）时，在14p处发现了强大的全基因组信号，其LOD为2.9，仅当只有两个OCD概率具有两个OCD概率时就会进一步增加包括或更多具有ho积的亲戚（LOD = 3.7）（Samuels等，2007）。 在整个强迫症组中发现的原始3Q信号在ho积子样本中消失了，但在其余较大的非降压组中得到了增强。 这表明其他强迫症遗传研究中的某些异质性可能是由具有ho积特征的个体促成的。 我们小组和其他研究强迫症个体的临床特征的早期研究表明，强迫症的严重程度更大，合并症的患病率更高，包括社交恐惧症和躁郁症，不同的人格特征以及对ho积者的药物和行为疗法的相对不敏感性Al。，1996; Samuels等人，2006年； 已经证明了SERT和OCD，自闭症，ADHD，酗酒和躁郁症之间相当强的遗传关联（Murphy等，2004）。但是，与几乎所有候选基因研究一样，都有一些差异结果。这些神经精神疾病并不是任何一种基因的结果，而是在多个系统中的多个基因相互作用的多个基因的遗传复杂构型。 Sert变体参与这些疾病的证据增加了与5-羟色胺相关的基因引起血清素系统功能改变（例如TPH2，AADC，MAOA/B，HTR1A）和其他5-羟色胺受体基因的可能性。 FEV，LMX1B，ITG3，BDNF和其他人也可能导致该疾病。但是，目前对这些基因的功能变异的了解少，并且对它们的研究较少。 他们的探索似乎是考虑血清素能参与这些疾病和相关疾病的必要下一步。