The Genetics Of Obsessive Compulsive Disorder

强迫症（OCD）是一种严重的遗传性疾病，其终生患病率约为人口的2%。遗传模式尚不清楚，但可能很复杂，涉及多个小到中等影响的位点。我们的实验室在强迫症及其遗传学研究方面已经活跃了超过15年，并于2001年成为强迫症多中心遗传研究的创始地点之一（p.a.：约翰霍普金斯大学的Gerald Nestadt博士）。这项研究是通过竞争激烈的NIMH校外资助申请批准的。由于支持基因对强迫症的贡献的证据的积累，一系列候选基因的关联研究已经进行并在文献中报道，但只有一个，非常小的强迫症全基因组扫描之前被报道过。我们在NIMH IRP中的强迫症基因研究为这项全国多位点全基因组强迫症研究提供了DNA和家族评估数据，该研究描述了其方法（Samuels等人，2006），并报告了今年10cM基因组扫描的第一批结果（Shugart等人，2006）。？对3q27 ~ 28 （P=0.0003）、6q （P=0.003）、7p （P=0.001）、1q （P=0.003）、15q （P=0.006）染色体进行多点分析，发现提示连锁信号。使用“宽泛”的强迫症定义，最有力的证据是在染色体3q27-28上发现的。最大的总体Kong和Cox LODall评分（2.67）出现在D3S1262和D3S2398，这两个信号基于模拟的p值分别为0.0003和0.0004，尽管这两个信号基于模拟的全基因组显著性水平均为0.055。协变量连锁分析暗示1号染色体上的基因可能在增加早期发病形式强迫症的风险中起作用。目前，该合作小组正在研究这五个区域的精细图谱，这些区域给出了暗示性信号，特别关注3q27-28。考虑到强迫症可能的病因异质性，可以通过复制研究、大规模家庭连锁研究和新统计方法的应用来增强与该疾病相关的基因定位。

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.)