2/3 Brain Function and Genetics in Pediatric Obsessive-Compulsive Behaviors

2/3 儿童强迫行为的脑功能和遗传学

• 批准号: 9098846
• 负责人: Gregory L. HANNA
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-11 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098846
• 关键词: Adolescent; Adopted; Advocate; Age; Anterior; Architecture; Behavior; Biological; Brain; CBL gene; Child; Child Behavior Checklist; Childhood; Clinical Research; Clinical assessments; Cognitive; Consensus; Corpus striatum structure; Data; Diagnosis; Disease; Dorsal; Family; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Gender; Genes; Genetic; Genetic Variation; Genetic study; Genomic approach; Genomics; Genotype; Goals; Grooming; Health; Heritability; Hospitals; Image; Individual; Lead; Magnetic Resonance Imaging; Measures; Medial; Mediating; Mental disorders; Michigan; Modeling; Molecular Genetics; Monitor; National Institute of Mental Health; Network-based; Neurobiology; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Outpatients; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Prevention strategy; Process; Psychopathology; Research; Research Design; Research Domain Criteria; Research Project Grants; Rest; Short-Term Memory; Site; Structure; Thalamic structure; Twin Studies; Universities; Variant; Work; Youth; age group; aged; arm; autism spectrum disorder; base; behavior influence; cingulate cortex; clinically significant; cognitive control; cognitive process; cost effective; effective therapy; effectiveness trial; frontal lobe; generalized anxiety; genetic variant; genome sequencing; genome-wide; imaging genetics; improved; neural circuit; neuropsychiatric disorder; novel; novel diagnostics; performance site; pleiotropism; prevent; programs; rare variant; response; risk variant; therapy development; trait; translational approach; whole genome

 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.

 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) 的核心特征之外，OCB 还常常与青少年抽动症、梳理行为、广泛性焦虑和自闭症谱系障碍有关。这一具有竞争力的更新应用程序结合了三个表演地点的独特临床评估、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) 和多伦多大学 (UT) 附属病童医院。该项目的总体目标是扩展先前和现有的 NIMH 资助的研究，包括博士。 Rosenberg 和 Diwadkar 的神经诊断成像遗传学研究（K24MH02037；R01MH59299），Hanna 博士的家族、分子遗传学和行为监测研究（R01MH53876；R01MH59299；K20MH01065；R01MH101493）以及 Arnold 和 同事们对儿科强迫症的广泛遗传学研究（R01MH59299；R01MH101493） - 旨在利用新兴的成像遗传学领域来1）确定通过任务和静息状态功能磁共振成像（fMRI）测量的额叶-纹状体-丘脑回路（FSTC）功能连接的改变与童年之间的关系 组织机构； 2) 识别与通过功能磁共振成像测量的 FSTC 连接性改变相关的常见、罕见和新颖的遗传变异； 3) 通过确定 fMRI 测量的 FSTC 改变是否介导遗传变异对 OCB 的影响，阐明它们是否是 OCB 潜在的中间表型； 4) 结合本研究的结构 MRI 数据和我们之前的成像遗传学研究，以确定与 1000 名青少年的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) 在儿科双胞胎研究中显示出显着的遗传性。 STC 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 的针对性高场 (3 Tesla) fMRI 将与综合基因组评估相结合，对 200 名 CBCL-OCS 评分 = 5 的儿童精神科门诊患者、200 名 CBL-OCS 评分 < 5 的儿童精神科门诊患者以及 200 名 8-18 岁的匹配健康对照患者进行综合评估。我们将检查与 FSTC 失调相关的常见和罕见基因组变异，并对分布最高 10% 的 60 名 FSTC 失调受试者进行全基因组测序 (WGS)，并与分布最低 10% 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变异。这项独特的研究通过检查 FSTC 中一系列常见但尚未充分研究的青少年疾病中的多个基因组变异，呼吁采用 PAR-14-165 中概述的转化方法来治疗精神疾病。我们的工作将更好地了解 OCB 发病机制中遗传变异对 FSTC 失调的影响，并带来新的诊断、治疗和预防策略。