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.

在过去的二十年里，我们特别关注的疾病一直是强迫症。 然而，由于强迫症与其他焦虑/抑郁症一样，表现出与多种疾病的高度共病，因此考虑到我们在人类中的基因 e 环境和基因 x 基因研究以及间接在小鼠模型中的研究，神经精神疾病本身的合并症一直是一个额外的特别关注点。 我们对 Sert 靶向小鼠（以及我们的合作者和同事的研究）的研究继续表明，Sert 基因功能被破坏的小鼠的多种表型与拥有至少五种功能性 SERT 变体的人类小鼠的多种表型之间有许多相似之处。 强迫症 (OCD) 是一种严重的遗传性疾病，世界人口的终生患病率约为 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基因座。我们的实验室 15 年来一直积极致力于强迫症及其遗传学研究，并于 2001 年成为强迫症多中心遗传学研究的创始地点之一（主要负责人：约翰·霍普金斯大学的 Gerald Nestadt 博士）。这项研究通过竞争性的 NIMH 校外拨款申请获得批准。 由于支持强迫症遗传因素的证据不断积累，一系列候选基因的关联研究已经进行并在文献中报道，但之前只报道过一次非常小的强迫症全基因组扫描。我们在 NIMH IRP 中的强迫症遗传学研究为这项全国性多地点、全基因组强迫症研究贡献了 DNA 和家庭评估数据，该研究描述了其方法（Samuels 等，2006），并报告了去年 10cM 基因组扫描的第一个结果（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) 的多点分析揭示了提示性连锁信号。使用“广义”强迫症定义，在染色体 3q27-28 上发现了最强有力的连锁证据。 Kong 和 Cox LODall 总得分最高 (2.67) 出现在 D3S1262 和 D3S2398，这两个信号的基于模拟的 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着性水平为 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病风险中发挥作用。 该合作小组目前正在五个区域进行精细绘图，以提供暗示性信号，特别关注 3q27-28。鉴于强迫症可能存在病因异质性，通过重复研究、大规模基于家族的连锁研究和新统计方法的应用，可以增强与该疾病相关的基因图谱。 此外，在 NIMH-IRP 内，对 300 名强迫症先证者及其 700 名患有或不患有强迫症相关疾病的亲属的 DNA、临床性格和其他特征进行探索性分析，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，对我们实验室的 317 名强迫症患者中每人的 70 种强迫症症状进行了因子和聚类分析，揭示了症状的四组因素，这些症状显示了与共存精神疾病的特定关系。 因此，因子 I（攻击性、性、宗教和身体强迫症以及检查强迫症）与共病焦虑症和抑郁症广泛相关。患有双相情感障碍和恐慌症/广场恐惧症的因子 II（对对称性的痴迷，以及重复、计数和排序/排列强迫症）；因素III（污染强迫症和清洁强迫症）与饮食失调有关。因素 I 和 II 与早发强迫症有关。强迫症与其他精神疾病频繁共存，以及强迫症症状维度与共存疾病之间相对具体的关联模式支持强迫症亚型对于这种异质性疾病的遗传、治疗和其他研究的重要性。 在本研究的基于基因的后续研究中，SERT 5HTTLPR 功能多态性与强迫症症状的对称/计数/排序（因子 II）维度之间存在关联。 在对 OCD 和抽动秽语综合症等相关疾病中的 SERT 基因的进一步研究中，病例对照研究和基于家庭的三人组研究发现 5HTTLPR 以及其中新发现的 SNP (rs25531) 与 OCD 相关。 报道了对强迫症的这些变异和其他变异进行基因分型的改进方法。 OCGS 选择了一个亚表型，即囤积，用于整个基因组的二次评估，基于先前的数据，囤积行为代表了该同胞对样本中家族性的强迫症维度（Hasler 等，2006），并且可能代表值得进一步研究的独特亚表型（Frost 等，1996；Samuels 等，2006；LaSalle-Ricci 等， 2006年； 张等人，2002；惠顿等人，2007）。 当 OCGS 强迫症样本仅限于那些有囤积癖和强迫行为的人（占总样本的 38%）时，在 14p 处发现了强烈的全基因组信号，LOD 为 2.9，当仅包括那些有两个或更多亲属有囤积行为的强迫症先证者时，该信号进一步增加（LOD = 3.7）（Samuels 等，2007）。 在整个强迫症组中发现的原始 3q 信号在囤积子样本中消失，但在剩余较大的非囤积组中增强。 这表明其他强迫症遗传研究中的一些异质性可能是由具有囤积特征的个体造成的。 我们小组和其他人对强迫症患者临床特征的早期研究表明，强迫症患者的强迫症严重程度更高，包括社交恐惧症和双相情感障碍在内的共病患病率更高，囤积者的性格特征不同，对药物和行为治疗相对不敏感（Frost 等人，1996 年；Samuels 等人，2006 年；LaSalle-Ricci 等人，2006 年；Wheaton 等人，2007 年； 克罗默等人，2006） SERT 与强迫症、自闭症、多动症、酗酒和双相情感障碍之间存在相当强的遗传关联已被证明（Murphy 等，2004）。然而，正如几乎所有候选基因研究一样，存在一些不一致的结果。这些神经精神疾病不被认为是任何一个基因的结果，而是多个系统中多个基因相互作用的遗传复杂配置。 SERT 变异参与这些疾病的证据提出了一种明显的可能性，即导致血清素系统功能改变的血清素相关基因（如 TPH2、AADC、MAOA/B、HTR1A）和其他血清素受体基因，以及 FEV、LMX1b、ITG3、BDNF 等也可能导致该疾病。然而，目前人们对这些基因的功能变异知之甚少，而且对它们的研究也不够全面。 他们的探索似乎是考虑血清素能参与这些及相关疾病的必要的下一步。