1 of 2: Identification of Rare Variants of OCD

描述（由申请人提供）：强迫症（OCD）是最常见的和失能的精神疾病之一。目前，强迫症的原因尚不清楚，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。这是一个在分子和患者水平上研究强迫症的合作提案。到目前为止，在强迫症的人类遗传学研究既没有确定一个基因位点的主要影响使用连锁研究，也没有发现常见的变异与条件使用GWAS研究。鉴于技术进步允许大规模测序，现在有机会检测这种遗传复杂疾病的推定罕见功能突变。在本申请中，我们建议直接检验假设 罕见的变异通过使用尖端的下一代全基因组测序技术来影响这种疾病。通过对最有可能表现出罕见突变的大型多重家族中的150个病例进行测序，将提高识别与强迫症相关的变异的效率。将使用贝叶斯多变异倾向性回归模型，根据其在正常对照中的频率、其功能注释、其保守性、其在病例中的富集以及其关于连锁峰和GWAS信号的基因组位置，对变异体进行优先排序。研究中的多重家庭将被重新联系和评估，以确定在首次调查时尚未超过风险年龄的其他亲属。 家庭评估。识别额外的受影响者将提高每个家族中连锁分析的灵敏度，这增强了变体的优先级。随后，将使用大规模iSelect芯片，在800名无关的OCD病例和750名对照以及每个多重家族中的两名亲属的独立样本中对8，000个候选变体进行基因分型，以识别潜在的致病变体。此外，将使用MiSeq平台对相关基因进行测序，以识别相同基因内具有不同致病变体的病例。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的领域，并为开发更有效的强迫症治疗方法提供新的策略。

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 recontacted 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.