2/2 - Identification of rare variants of OCD

描述（由申请人提供）：强迫症（OCD）是最常见的精神障碍之一。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建议。到目前为止，强迫症的人类遗传研究既没有通过连锁研究确定一个具有主要影响的遗传位点，也没有通过GWAS研究发现与强迫症相关的常见变异。鉴于技术的进步，允许大规模测序，现在有机会检测这种遗传复杂疾病的假定罕见功能突变。在这个应用中，我们建议直接检验假设

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.