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使识别导致疾病的变异变得困难。家庭测序，特别是对患病儿童和未患病父母的三重奏和四重奏进行排序，使人们能够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出现的少数新生或罕见和纯合的变异。越来越多的人认识到，这是研究复杂疾病的一种富有成效的方法。在这里，我们建议在家系中进行完整的外显子组测序，以确定易患强迫症(OCD)的遗传变异。强迫症是全球十大致残性疾病之一，涉及持续的、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)。据估计，强迫症的终生患病率为1-3%。尽管自20世纪80年代末就可以使用的药物和行为疗法很有用，但它们控制症状的效果有限，而且在大多数情况下，病情的病程仍然是慢性的；治愈的可能性很小。因此，了解强迫症的病理生理学机制是至关重要的，这样我们才能最终开发有效的治疗方法。我们建议对375个单纯性强迫症三联体和100个强迫症四重组的外显子进行测序，其中包括受影响的同胞和未受影响的双亲。在三人组中，我们将识别被注释为功能性的从头变体。即使发现从头开始的变异只解释一小部分强迫症病例，它们的发现将为理解这种疾病的病理生理学提供实质性的进步。此外，我们将分析在三人组中发现的新变异体的分布，将这一分布与普通人群中的预期分布进行比较。 在其他精神疾病的三人组中也发现了这种情况。在四重奏和三重奏中，我们将识别在后代中是纯合子的或复合杂合的，但在父母中是杂合的因果变异。我们将确定落入这些类别的候选变体，并根据功能注释、不相关家族之间相关基因的稀有性和重叠来确定它们的优先级。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因果变异的无关病例之间共享的特征，以及通过寻找明确定义的临床亚组患者(如抽动障碍患者)的遗传相似性，来确定基因型与表型的相关性。

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.