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

通过全外显子组测序识别三人组中引起强迫症的从头突变

• 批准号: 8994339
• 负责人: David B. Goldstein
• 金额: $ 12.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994339
• 关键词: Identifying; de; novo; mutations; causing

DESCRIPTION (provided by applicant): The wealth of information provided by whole-exome and whole-genome sequencing studies can make it difficult to pick out the variants that cause disease. Family sequencing, in particular the sequencing of trios and quartets with affected children and unaffected parents, allows one to remove most of the rare variants that are 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 an important method 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 will 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 a small proportion of OCD cases, the general rarity of de novo variants that are annotated as functional should facilitate the discovery of causal de novo variants when they exist. Furthermore, the sequencing of trios (and quartets) allows for the identification of 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 look for characteristics that are shared between unrelated cases with causal variants in the same gene.

描述（由申请人提供）：全异构体和全基因组测序研究提供的大量信息可能会使很难挑选引起疾病的变体。家庭测序，尤其是三重奏和四重奏与受影响的孩子和未受影响的父母的测序，使人们可以删除基因组中存在的大多数稀有变体，并专注于从头或稀有和稀有且仅在偏远地区中的纯合子。人们越来越认识到这是复杂疾病研究中的重要方法。在这里，我们建议在家族中进行全外显子体测序，以鉴定易感强迫症（OCD）的遗传变异。强迫症是全球最禁用的医疗状况中的10种，涉及持久，侵入性，无意义的思想和冲动（痴迷）和重复性，故意的行为（强迫）。 OCD的寿命患病率估计为1-3％。尽管自1980年代后期以来可用的药物和行为疗法是有用的，但它们仅控制成功的症状，并且在大多数情况下，病情的过程仍然慢性；治愈是罕见的。因此，了解强迫症的病理生理学至关重要，因此我们最终可以开发有效的治疗方法。我们将对包括受影响的SIB和未受影响的父母组成的375个单纯型OCD三重奏和100个OCD四重奏的外来组成。在这三重奏中，我们将确定从头注释的函数的变种。即使发现从头变体可以解释一小部分的强迫症病例，但被注释为功能的从头变体的一般稀有性应促进发现 从新生变体存在时。此外，三重奏（和四重奏组）的测序允许鉴定后代中纯合或复合杂合的因果变体，但在父母中是杂合的。我们将确定属于这些类别的候选变体，并根据功能注释，稀有性和无关家族之间牵连基因的重叠来确定它们的优先级。然后，我们将通过在未受影响的家庭成员中对这些变体进行基因分型来确认这些变体。最后，我们将寻找在同一基因中具有因果变异的无关病例之间共享的特征。