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）是一种严重的遗传性疾病，终生患病率约为人口的2%。遗传方式还不清楚，但可能很复杂，涉及多个小到中等影响的基因座。我们的实验室已经积极研究强迫症及其遗传学超过15年，并在2001年成为一个多中心的强迫症遗传学研究的创始地点之一（P.I.：约翰霍普金斯大学的Gerald Nestadt博士）。本研究通过竞争性NIMH校外资助申请获得批准。由于支持遗传对强迫症的贡献的证据的积累，已经进行了一系列候选基因的关联研究并在文献中报道，但以前只报道了一个非常小的强迫症全基因组扫描。我们在NIMH IRP中的OCD遗传学研究将DNA和家族评估数据贡献给这个国家多位点、全基因组的OCD研究，该研究描述了其方法（Samuels等人，2006），并在今年报道了来自10cM基因组扫描的第一个结果（Shugart等人，2006年）。?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）上的多点分析揭示了提示连锁信号。使用"广义"强迫症定义，最强有力的连锁证据被发现在染色体3q27 - 28。最大总体Kong和考克斯LODall评分（2.67）发生在D3S1262和D3S2398，这两个信号基于模拟的P值分别为0.0003和0.0004，尽管对于这两个信号，基于模拟的全基因组显著性水平为0.055。协变量连锁分析表明，1号染色体上的基因可能在增加强迫症早期发作的风险中起作用。该合作小组目前正在五个区域进行精细定位，给出暗示性信号，特别关注3q27 - 28。考虑到强迫症可能的病因异质性，通过复制研究、大规模的以家族为基础的连锁研究和新的统计方法的应用，可能会加强与强迫症相关的基因定位。 此外，在NIMH-IRP中，对约300名强迫症先证者和与强迫症相关的疾病的DNA、临床特征和个性以及其他特征的探索性分析被用于评估基因变异的候选状态，并更好地定义家族性强迫症表型。 在一项这样的研究中，对来自我们实验室的317名患有强迫症的患者中的每一个中评定的70种强迫症症状的因子和聚类分析揭示了症状的四因子分组，其显示出与共病精神障碍的特定关系（Hasler等人，2005年）。因此，因子I（攻击性、性、宗教和躯体强迫观念，以及检查强迫）与共病焦虑症和抑郁症广泛相关;因子II（对称强迫观念，以及重复、计数和排序/安排强迫）与双相情感障碍和惊恐障碍/广场恐怖症广泛相关;因子III（污染强迫观念和清洁强迫）与进食障碍广泛相关。因子I和因子II与早发性强迫症相关。强迫症与其他精神疾病的频繁共存以及强迫症症状维度与共病疾病之间相对特定的关联模式支持强迫症亚型对这种异质性疾病的遗传、治疗和其他研究的重要性。在对该研究的基于基因的随访中，在SERT 5HTTLPR功能多态性和OCD症状的对称性/计数/排序（因子II）维度之间复制了关联（Hasler等人，2006年）。在进一步研究SERT基因在强迫症和相关疾病，如妥瑞症？s综合征，在病例对照和三重研究中发现5HTTLPR与其中新发现的SNP（rs25531）一起与OCD相关（Hu et al.，2006），并且报道了对OCD中的这些和其它变体进行基因分型的改进方法（Wendland等人，2006年a; 2006年b）