Identifying de novo mutations causing OCD in trios by whole exome sequencing

描述（由申请人提供）：全外显子组和全基因组测序研究提供的丰富信息可能难以识别导致疾病的变异。家族测序，特别是对受影响儿童和未受影响父母的三胞胎和四胞胎的测序，允许排除基因组中存在的大多数罕见变异，并专注于仅在后代中新生或罕见和纯合的少数变异。越来越多的人认识到，这是研究复杂疾病的一种有效方法。在这里，我们建议在家庭中进行全外显子组测序，以确定易患强迫症（OCD）的遗传变异。强迫症是世界上10种最致残的医学疾病之一，涉及持久的，侵入性的，无意义的想法和冲动（强迫症）以及重复的故意行为（强迫症）。强迫症的终生患病率估计为1- 3%。虽然药物治疗和行为治疗，自20世纪80年代末以来，是有用的，他们控制症状只有有限的成功，在大多数情况下，病情的过程仍然是慢性的;治愈是罕见的。因此，了解强迫症的病理生理学至关重要，这样我们才能最终开发出有效的治疗方法。我们建议对375个单纯强迫症三人组和100个强迫症四人组（包括受影响的同胞和未受影响的父母）的外显子组进行测序。在三人组中，我们将鉴定被注释为功能性的从头变异。即使发现新生变异只能解释一小部分强迫症病例，它们的发现也将为理解这种疾病的病理生理学提供实质性的进展。此外，我们还将分析在三人组中发现的新发变异的分布，并将该分布与一般人群中的预期分布进行比较 和其他精神疾病的三人组中发现的。在四联体和三联体中，我们将鉴定在后代中为纯合或复合杂合但在亲本中为杂合的因果变异。我们将确定属于这些类别的候选变体，并根据功能注释、稀有性和不相关家族之间相关基因的重叠对其进行优先排序。然后，我们将通过对未受影响的家庭成员进行基因分型来确认这些变异。最后，我们将通过寻找具有相同基因中的因果变异的不相关病例之间共享的特征，以及通过在明确定义的临床患者亚组（如抽动障碍患者）中寻找遗传相似性，来确定基因型-表型相关性。

DESCRIPTION (provided by applicant): The wealth of information provided by whole-exome and whole-genome sequencing studies can make it difficult to identify variants that cause disease. Family sequencing, in particular the sequencing of trios and quartets with affected children and unaffected parents, allows one to exclude most of the rare variants present in the genome and focus on those few that are de novo or rare and homozygous only in the offspring. There is growing recognition that this is a productive approach in the study of complex diseases. Here, we propose to perform whole exome sequencing in families to identify genetic variants predisposing to obsessive-compulsive disorder (OCD). OCD is among the 10 most disabling medical conditions worldwide and involves persistent, intrusive, senseless thoughts and impulses (obsessions) and repetitive, intentional behaviors (compulsions). The lifetime prevalence of OCD is estimated at 1-3%. Although medication and behavioral therapy, available since the late 1980s, are useful, they control symptoms with only limited success, and the course of the condition remains chronic in most cases; cure is rare. It is therefore critical to understand the pathophysiology of OCD so we can ultimately develop effective treatments. We propose to sequence the exomes of 375 simplex OCD trios and 100 OCD quartets comprising affected sibs and unaffected parents. In the trios, we will identify de novo variants that are annotated as functional. Even if de novo variants are found to explain only a small proportion of OCD cases, their discovery will provide a substantial advance in understanding the pathophysiology of the disorder. Furthermore, we will analyze the distribution of de novo variants found in the trios, comparing this distribution to that expected in the general population and that found in trios from other psychiatric diseases. In the quartets as well as the trios, we will identify causal variants that are homozygous or compound heterozygous in the offspring but heterozygous in the parents. We will identify candidate variants falling into these categories and will prioritize them based upon functional annotation, rarity and overlap of implicated genes between unrelated families. We will then confirm these variants by genotyping them in unaffected family members. Finally, we will identify genotype-phenotype correlations by looking for characteristics that are shared between unrelated cases with causal variants in the same gene and also by looking for genetic similarities within clearly defined clinical subgroups of patients, such as those with tic disorders.