2/2 - Identification of rare variants of OCD

描述(申请人提供)：强迫症(OCD)是最常见和最丧失能力的精神障碍之一。目前，强迫症的病因尚不清楚，虽然有治疗方法，但没有特效药。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建议。到目前为止，强迫症的人类遗传学研究既没有使用连锁研究确定具有主要影响的遗传位点，也没有使用GWAS研究发现与这种疾病相关的常见变异。鉴于技术的进步使得大规模测序成为可能，现在有机会为这种复杂的基因疾病检测假定的罕见功能突变。在此应用程序中，我们建议直接检验假设 这种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基因家族中的150例病例进行测序，将提高识别与强迫症相关的变异的效率。将使用贝叶斯多变量倾向回归模型，根据它们在正常对照中的频率、它们的功能注释、它们的保守性、它们在病例中的丰富度以及它们在连接峰和Gwas信号方面的基因组位置来确定变异的优先顺序。研究中的多子女家庭将被重新联系和评估，以确定在最初感染时还没有过风险年龄的其他亲属。 家庭评估。识别更多的受影响因素将提高每个家族中连锁分析的敏感性，从而增强变异的优先顺序。随后，将使用大规模的iSelect芯片，在800例无关的强迫症病例和750名对照以及每个多基因家族的两名亲属的独立样本中对8000个候选变异进行基因分型，以确定潜在的致病变异。此外，涉及的基因将使用MiSeq平台进行测序，以确定同一基因中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领域，并将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 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.