Action Monitoring and Genomic Variants in Pediatric Obsessive-Compulsive Behavior

描述（由申请人提供）：强迫症（OC）行为在青少年中很常见。它们是强迫症（OCD）的核心特征，通常在青少年中与抽动和梳理障碍、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，因为它将检查OC行为和错误相关的负性（ERN）作为儿童精神科门诊患者的绩效监测措施-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是结合

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.