The Genetics Of Obsessive Compulsive Disorder

强迫症的遗传学

• 批准号: 7304034
• 负责人: DENNIS L MURPHY
• 金额: --
• 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/7304034
• 关键词: Genetics; Obsessive; Compulsive; Disorder

Obsessive-compulsive disorder (OCD) is a severe, heritable condition with a lifetime prevalence of about two percent of the population. 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 this 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 gene(s) 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 features and personality and other characteristics of ~300 OCD probands and of disorders related to OCD 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 (Hasler et al., 2005). 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 (Hasler et al., 2006). In further studies of the SERT gene in OCD and related disorders such as Tourette?s 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 trios study (Hu et al., 2006) and improved methods to genotype these and other variants in OCD were reported (Wendland et al., 2006a; 2006b.)

强迫症（OCD）是一种严重的，可遗传的疾病，终生患病率约为2％。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OCD的全国多站点全基因组研究提供了DNA和家庭评估数据，该研究描述了其方法（Samuels等，2006），并报告了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）和15q（p = 0.006），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。给定强迫症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吗？ 此外，在NIMH-IRP中，对DNA，临床特征和个性以及〜300 ocd概率的临床特征和个性以及其他特征的探索性分析以及与OCD相关的疾病的探索性分析可用于评估基因变体的候选状态，并更好地定义家族性OCD表型。 在一项这样的研究中，对我们实验室的317例强迫症患者中每名级的70例OCD症状的因子和聚类分析显示，症状的四个因子分组，这些因素与合并症的精神疾病显示了特定关系（Hasler等，2005）。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）维度（因素II）维度（Hasler等，2006）之间复制了关联。在进一步研究强迫症和相关疾病（例如Tourette？s综合征）中的SERT基因时，发现5HTTLPR以及其中的新发现的SNP（RS25531）在其中发现与Case-Control研究和三架研究中的OCD有关（Hu等，2006）和改进了OCD中这些变体的基因型和其他变体的改进方法（Wendland等，2006a; 2006b。）。