Action Monitoring and Genomic Variants in Pediatric Obsessive-Compulsive Behavior

描述（由申请人提供）：强迫症（OC）行为在青年中很常见。它们是强迫症（OCD）的核心特征，在年轻人中通常与抽动和修饰障碍、广泛性焦虑症和自闭症谱系障碍有关。本提案是为了响应RFA-MH-13-080《精神疾病研究分类的维度方法》而提交的，因为它将在儿童精神病门诊患者中检查OC行为和错误相关消极性（ERN），作为性能监测的一项指标-研究领域标准（RDoC）矩阵的认知系统领域中的认知控制结构。该项目的总体目标-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作为涉及前扣带皮层（ACC）和前辅助运动区的神经回路的指标，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）表征的OC行为的危险因素。CBCL-OCS和ERN在儿科双胞胎研究中均显示出显著的遗传性。虽然在确定与OC行为相关的电生理和遗传因素方面取得了进展，但很少解释遗传变异，并且对这些变异的神经生物学后果知之甚少。与其他复杂性状一样，越来越多的人认为，基因发现可以通过使用内在表型来促进，内在表型位于遗传风险因素和症状之间的因果通路上。大量研究表明，扩大的ERN是一种状态独立的性状，在OC行为患者及其未受影响的亲属中发现的比例高于一般人群，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名具有突出OC行为的儿童精神病门诊患者，150名具有可忽略OC行为的儿童精神病门诊患者和150名年龄8-18岁的匹配健康对照者中进行检查，以描述ERN与青少年OC行为的关系，使用抽动史和抑郁严重程度作为协变量。第二，将在550名受试者（包括已经收集的100名受试者）的样本中鉴定与ERN振幅相关的常见和罕见外显子变体，使用具有广泛覆盖的外显子标志物的外显子组阵列。第三，将在ERN振幅分布最高5%的受试者中进行WGS，以识别可能具有临床意义的罕见和新型变体。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。这项研究将在一个重要的神经回路中检查目标导向行为的多个变体， 一系列常见但研究不足的青年疾病。我们的工作将提供一个更好的理解ACC失调的发病机制，儿童OC行为，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.