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: 9265510
• 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/9265510
• 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; Dimensions; Disease; Dorsal; Family; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Gender; Genes; Genetic; Genetic Variation; Genetic study; Genomic approach; Genomics; Genotype; Goals; Grooming; 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; 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; efficacy trial; frontal lobe; generalized anxiety; genetic variant; genome sequencing; genome-wide; imaging genetics; imaging study; improved; neural circuit; neuropsychiatric disorder; novel; novel diagnostics; performance site; pleiotropism; prevent; programs; public health relevance; rare variant; response; risk variant; therapy development; trait; translational approach; treatment strategy; 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(申请人提供)：强迫症(OCB)在儿童和青少年中很常见。除了强迫症(OCD)的核心特征外，OCB在年轻人中经常与抽搐、修饰、广泛性焦虑和自闭症谱系障碍联系在一起。这一竞争性续签申请结合了三个绩效网站独特的临床评估、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)附属的患病儿童医院。这个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-遗传学研究(K24MH02037；R01MH59299)，Hanna博士的家庭、分子遗传和行动监测研究(R01MH53876；R01MH59299；K20MH01065；R01MH101493)以及Arnold博士和他的同事在儿童OCD中进行的广泛的遗传学研究(R01MH59299；R01MH101493)--利用成像遗传学的新兴领域1)确定通过任务和静止功能磁共振成像(FMRI)测量的额叶到纹状体-丘脑回路(FSTC)的功能连接变化与儿童OCB之间的关系；2)找出与fMRI测量的FSTC连接性改变相关的常见的、罕见的和新的遗传变异；3)通过确定它们是否中介遗传变异对OCB的影响，阐明fMRI测量的FSTC的改变是否是OCB的潜在中间表型；以及4)结合本研究的结构MRI数据和我们先前的成像遗传学研究，在1000名青年中确定与前扣带回体积和其他FSTC结构相关的遗传变异。儿童行为量表强迫量表(CBCL-OCS)在儿科双胞胎研究中显示出很大的遗传性。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，威斯康星州立大学的靶向高场(3特斯拉)功能磁共振成像将与全面的基因组评估相结合，纳入200名CBCL-OCS评分为5分的儿童精神科门诊患者，200名CBL-OCS评分为5分的儿童精神科门诊患者，以及200名8-18岁的匹配健康对照组。我们将检查与FSTC异常相关的常见和罕见的基因组变异，并对分布在最高10%的60名FSTC异常的受试者进行全基因组测序(WGS)，并与60名分布在最低10%的FSTC异常的受试者进行比较，以确定可能具有临床意义的罕见和新的变异体。这项独特的研究通过检查FSTC中的多个基因组变异，制定了PAR-14-165中概述的精神疾病的翻译方法的呼吁，这些变异发生在一系列常见但未被研究的青年疾病中。我们的工作将使我们更好地理解遗传变异在OCB发病机制中对FSTC失调的影响，并导致新的诊断、治疗和预防策略。