Action Monitoring and Genomic Variants in Pediatric Obsessive-Compulsive Behavior

描述(申请人提供)：强迫症(OC)行为在青少年中很常见。它们是强迫症(OCD)的核心特征，在年轻人中经常与抽动和梳理障碍、广泛性焦虑症和自闭症谱系障碍联系在一起。本提案是针对RFA-MH-13-080，《精神疾病研究分类的维度方法》提出的，因为它将检查儿童精神科门诊患者的OC行为和错误相关负性(ERN)，作为绩效监测的一种衡量标准--研究领域标准(RDoC)矩阵中认知系统领域的认知控制结构。这个项目的总体目标--它结合了 我们在儿童精神病理学、心理生理学和遗传学方面的专业知识-是使用ERN作为涉及前扣带回(ACC)和辅助运动区前区域的神经回路的索引，以及外显子组阵列和全基因组测序(WGS)的最新进展，以确定儿童行为检查表OC量表(CBCL-OCS)特征的OC行为的风险因素。CBCL-OCS和ERN在儿科双生子研究中都显示出显著的遗传性。尽管在识别与OC行为相关的电生理和遗传因素方面取得了进展，但对遗传变异的解释很少，这些变异的神经生物学后果也鲜为人知。与其他复杂的性状一样，人们越来越一致地认为，可以通过利用内表型来促进基因发现，内表型取决于遗传风险因素和症状之间的因果关系。大量研究表明，ERN的增大是一种状态独立的特征，在有OC行为的患者及其未受影响的亲属中的发生率高于普通人群，这为ERN作为OC行为的候选内表型提供了强有力的支持。与RDoC项目一致，ERN将首先在150名OC行为突出的儿童精神科门诊患者、150名OC行为可忽略的儿童精神科门诊患者和150名8-18岁的匹配健康对照组中进行检查，以抽动病史和抑郁严重程度为协变量，描述ERN与青少年OC行为的关系。其次，将使用广泛覆盖外显子标记的外显子阵列，在550名受试者(包括已收集的100名受试者)样本中识别与ERN幅度相关的常见和罕见外显子变体。第三，WGS将在ERN波幅在分布的最高5%的受试者中进行，以识别可能具有临床意义的罕见和新的变异。第四，ERN作为一种内表型的作用将通过评估ERN是否介导遗传变异对OC行为的影响来阐明。这项研究将检查一个重要的神经回路中目标导向行为的多个变体 青少年常见但未被充分研究的疾病谱系。我们的工作将为更好地理解ACC失调在儿童OC行为发病机制中的作用，并导致新的预防和治疗策略。

DESCRIPTION (provided by applicant): Obsessive-compulsive (OC) behaviors are common in youth. They are the core features of obsessive- compulsive disorder (OCD) and are often associated in youth with tic and grooming disorders, generalized anxiety disorder, and autistic spectrum disorder. This proposal is submitted in response to RFA-MH-13-080, Dimensional Approaches to Research Classification in Psychiatric Disorders, since it will examine OC behaviors and the error-related negativity (ERN) as a measure of performance monitoring - a cognitive control construct in the cognitive systems domain of the Research Domain Criteria (RDoC) matrix - in child psychiatric outpatients. The overall goal of this project - which combines our expertise in child psychopathology, psychophysiology, and genetics - is to use the ERN as an index of a neural circuit involving the anterior cingulate cortex (ACC) and pre-supplementary motor area, as well as recent advances in exome arrays and whole genome sequencing (WGS), to identify risk factors for OC behaviors characterized by the Child Behavior Checklist OC Scale (CBCL-OCS). Both the CBCL-OCS and ERN show substantial heritability in pediatric twin studies. Although progress has been made in identifying electrophysiological and genetic factors associated with OC behaviors, little of the genetic variance has been explained and the neurobiological consequences of those variants are poorly understood. As with other complex traits, there is a growing consensus that gene discovery can be facilitated by using endophenotypes, which lie on the causal pathway between genetic risk factors and symptoms. Numerous studies have demonstrated that an enlarged ERN is a state-independent trait found in patients with OC behaviors and their unaffected relatives at a higher rate than in the general population, providing strong support for the ERN as a candidate endophenotype for OC behaviors. Consistent with the RDoC project, the ERN will be examined first in 150 child psychiatric outpatients with prominent OC behaviors, 150 child psychiatric outpatients with negligible OC behaviors, and 150 matched healthy controls ages 8-18 years to delineate the relationship of the ERN to OC behaviors in youth, using tic history and depression severity as covariates. Second, common and rare exonic variants associated with ERN amplitude will be identified in a sample of 550 subjects (including 100 subjects already collected), using an exome array with extensive coverage of exonic markers. Third, WGS will be done in subjects with ERN amplitudes in the highest 5% of the distribution to identify rare and novel variants of possible clinical significance. Fourth, the role of the ERN as an endophenotype will be clarified by assessing whether the ERN mediates the effects of genetic variants on OC behaviors. This study will examine multiple variants in an important neural circuit for goal-directed behavior in a spectrum of common but understudied disorders in youth. Our work will provide a better understanding of ACC dysregulation in the pathogenesis of childhood OC behaviors and lead to new prevention and treatment strategies.