2/2 - Identification of rare variants of OCD

2/2 - 识别强迫症的罕见变体

• 批准号: 8877316
• 负责人: GERALD NESTADT
• 金额: $ 35.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877316
• 关键词: Affect; Age; Area; Bayesian Modeling; Clinical Data; Collaborations; Complex; Data Linkages; Development; Disease; Drug Targeting; Etiology; Exhibits; Extended Family; Family; Family Study; Family member; Frequencies; Genes; Genetic; Genetic study; Genomic Segment; Genomics; Genotype; Health; Heritability; Human Genetics; Individual; Large-Scale Sequencing; Location; Mental disorders; Modeling; Molecular; Molecular Genetics; Mutation; Neurobiology; Obsession; Obsessive-Compulsive Disorder; Pathway interactions; Patients; Phenotype; Population; Property; Relative (related person); Research; Risk; Risk Factors; Sampling; Scientist; Signal Transduction; Syndrome; Technology; Testing; Thinking; Time; Universities; Variant; Weight; Work; base; case control; compulsion; effective therapy; field study; genetic linkage analysis; genetic pedigree; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; improved; insight; interest; member; next generation; novel; rare variant

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is one of the most common and incapacitating psychiatric disorders. Currently, the cause of OCD is unknown, and while treatments are available, there is no specific cure. Therefore, understanding the molecular and genetic mechanisms leading to OCD will be critical for the development of effective treatments. This is a collaborative proposal to study OCD at the molecular and patient levels. Thus far, human genetic studies in OCD have neither identified a genetic locus with a major effect using linkage studies nor found common variants associated with the condition using GWAS studies. Given the technological advances that permit large-scale sequencing, there is now the opportunity to detect putative rare functional mutations for this genetically complex condition. In this application, we propose to directly test the hypothesis that rare variants influence this disease by using cutting-edge next generation whole-genome sequencing technologies. The efficiency of identifying variants relevant for OCD will be increased by sequencing the 150 cases in large, multiplex families that are most likely to exhibit a rare mutation. Variants will be prioritized using a Bayesian multi-variant liability regression model based upon their frequency in normal controls, their functional annotation, their conservation, their enrichment in cases, and their genomic location with regard to linkage peaks and GWAS signals. The multiplex families in the study will be re-contacted and assessed to identify additional relatives who had not passed through the age of risk at the time of the initial family assessment. Identifying additional affecteds will improve the sensitivity of the linkage analysis in each family, this enhancing the prioritization of variants. Subsequently, 8,000 candidate variants will be genotyped in an independent sample of 800 unrelated OCD cases and 750 controls, as well as two relatives in each multiplex family, using a large-scale iSelect chip, to identify potentially causative variants. Additionally, implicated genes will be sequenced using the MiSeq platform to identify cases with different causal variants within the same genes. If successful, these studies will open up the field for neurobiology and human genetic studies of OCD and will provide insight for new strategies to develop more effective treatments for OCD.

描述（由申请人提供）：强迫症（OCD）是最常见且导致丧失行为能力的精神疾病之一。目前，强迫症的病因尚不清楚，虽然有治疗方法，但没有具体的治愈方法。因此，了解导致强迫症的分子和遗传机制对于开发有效的治疗方法至关重要。这是一项在分子和患者水平上研究强迫症的合作提案。迄今为止，强迫症的人类遗传学研究既没有利用连锁研究鉴定出具有重大影响的遗传位点，也没有利用 GWAS 研究发现与该病症相关的常见变异。鉴于允许大规模测序的技术进步，现在有机会检测这种遗传复杂疾病的假定罕见功能突变。在此应用中，我们建议直接检验假设 通过使用尖端的下一代全基因组测序技术，罕见变异会影响这种疾病。通过对大型、多重家族中最有可能表现出罕见突变的 150 个病例进行测序，将提高识别与 OCD 相关的变异的效率。将使用贝叶斯多变体责任回归模型根据变体在正常对照中的频率、功能注释、保守性、病例中的富集以及关于连锁峰和 GWAS 信号的基因组位置对变体进行优先级排序。研究中的多重家庭将被重新联系和评估，以确定在最初的时候尚未达到风险年龄的其他亲属 家庭评估。识别其他受影响者将提高每个家族连锁分析的敏感性，从而增强变异的优先顺序。随后，将使用大规模 iSelect 芯片对 800 个不相关的强迫症病例和 750 个对照以及每个多重家族中的两名亲属组成的独立样本中的 8,000 个候选变异进行基因分型，以识别潜在的致病变异。此外，将使用 MiSeq 平台对相关基因进行测序，以识别同一基因内具有不同因果变异的病例。如果成功，这些研究将为强迫症的神经生物学和人类遗传学研究开辟新领域，并将为开发更有效的强迫症治疗方法的新策略提供见解。