3/3 Brain Function and Genetics in Pediatric Obsessive-Compulsive Behaviors

 描述（由申请人提供）：强迫行为（OCB）在儿童和青少年中很常见。除了是强迫症（OCD）的核心特征外，OCB还经常与青少年的抽搐、修饰、广泛性焦虑和自闭症谱系障碍有关。这种竞争性的续期申请结合了三个性能站点的独特临床评估，磁共振成像和遗传学专业知识：韦恩州立大学（WSU），密歇根大学（UM）和附属于多伦多大学（UT）的儿童医院。该项目的总体目标是扩展先前和现有的NIMH资助的研究，包括Rosenberg博士和Diwadkar博士的神经诊断成像-遗传研究（K24MH02037; R01MH59299），Hanna博士的家族、分子遗传学和作用监测研究（R01MH53876; R01MH59299; K20MH01065; R01MH101493）和Arnold博士及其同事对儿童强迫症的广泛遗传研究（R01MH59299; R01MH101493）-是利用新兴的成像遗传学领域，以1）确定额-纹状体功能连接改变之间的关系，通过任务和静息状态功能性磁共振成像（fMRI）和儿童OCB测量丘脑回路（FSTC）; 2）识别与通过fMRI测量的FSTC连接改变相关的常见、罕见和新的遗传变异;第三章通过确定fMRI测量的FSTC改变是否介导遗传变异对OCB的影响，OCB;和4）结合联合收割机的结构MRI数据和我们以前的成像遗传学研究，以确定1000名青年中与前扣带回体积和其他FSTC结构相关的遗传变异。儿童行为检查表强迫量表（CBCL-OCS）在儿科双生子研究中显示出相当大的遗传性。STC的结构和功能异常的遗传性也在强迫症患者及其未受影响的亲属中得到证实。通过使用符合研究领域标准（RDoC）的研究设计，WSU的靶向高场（3特斯拉）fMRI将与200名CBCL-OCS评分= 5的儿童精神病门诊患者、200名CBL-OCS评分<5的儿童精神病门诊患者和200名年龄在8 - 18岁之间的匹配健康对照者的综合基因组评估相结合。我们将检查与FSTC失调相关的常见和罕见基因组变异，并在分布最高的10%中的60名FSTC失调受试者中进行全基因组测序（WGS），并与分布最低的10%中的60名FSTC失调受试者进行比较，以确定可能具有临床意义的罕见和新型变异。这项独特的研究通过在一系列常见但未充分研究的青年疾病中检查FSTC中的多个基因组变异，呼吁对PAR-14 - 165中概述的精神疾病进行翻译。我们的工作将提供一个更好的理解遗传变异的影响FSTC失调的发病机制OCB，并导致新的诊断，治疗和预防策略。

 DESCRIPTION (provided by applicant): Obsessive-compulsive behaviors (OCB) are common in children and adolescents. In addition to being the core features of obsessive-compulsive disorder (OCD), OCB are often associated in youth with tic, grooming, generalized anxiety, and autistic spectrum disorders. This competitive renewal application combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites: Wayne State University (WSU), University of Michigan (UM), and the Hospital for Sick Children, affiliated with the University of Toronto (UT). The overall goal of this project - which extends prior and existing NIMH-funded research including Drs. Rosenberg and Diwadkar's neurodiagnostic imaging-genetic studies (K24MH02037; R01MH59299), Dr. Hanna's family, molecular genetic, and action monitoring studies (R01MH53876; R01MH59299; K20MH01065; R01MH101493) and Dr. Arnold and colleagues' extensive genetic studies in pediatric OCD (R01MH59299; R01MH101493) - is to exploit the emerging field of imaging genetics to 1) determine the relationship between alterations in functional connectivity of fronto-striatal-thalamic circuitry (FSTC) as measured by task and resting state functional magnetic resonance imaging (fMRI) and childhood OCB; 2) identify common, rare, and novel genetic variants associated with alterations in connectivity of FSTC as measured by fMRI; 3) clarify whether fMRI measured alterations in FSTC are potential intermediate phenotypes of OCB by determining whether they mediate the effects of genetic variants on OCB; and 4) combine structural MRI data from this study and our previous imaging genetics study to identify genetic variants associated with anterior cingulate volume and other FSTC structures in 1000 youth. The Child Behavior Checklist Obsessive-Compulsive Scale (CBCL-OCS) shows substantial heritability in pediatric twin studies. Heritability of structural and functional abnormalities in STC has also been demonstrated in OCD patients and their unaffected relatives. By using a research design consistent with the Research Domain Criteria (RDoC), targeted high field (3 Tesla) fMRI at WSU will be combined with comprehensive genomic assessment in 200 child psychiatric outpatients with CBCL-OCS scores = 5, 200 child psychiatric outpatients with CBL-OCS scores < 5, and 200 matched healthy controls aged 8-18 years. We will examine for common and rare genomic variants associated with FSTC dysregulation and conduct whole genome sequencing (WGS) in 60 subjects with FSTC dysregulation in the highest 10% of the distribution and compare to 60 subjects with FSTC dysregulation in the lowest 10% of the distribution to identify rare and novel variants of possible clinical significance. This unique study enacts the call for translational approaches to mental illness outlined in PAR- 14-165 by examining multiple genomic variants in FSTC in a spectrum of common, but understudied disorders in youth. Our work will provide a better understanding of the impact of genetic variants on FSTC dysregulation in the pathogenesis of OCB and lead to new diagnostic, treatment, and prevention strategies.