2/3-Brain Chemistry and Genetics in Pediatric Obsessive-Compulsive Disorder

描述（由申请人提供）：这是韦恩州立大学首席研究员（罗森伯格）资助奖的竞争性更新申请，R01MH59299。强迫症（OCD）是一种严重的、普遍的、慢性致残的疾病，在儿童时期出现的病例多达50%。该项目的总体目标是结合三个表现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（儿科强迫症的神经成像），密歇根大学（早发性强迫症的家族和分子遗传学研究）和多伦多大学（强迫症中谷氨酸受体和转运基因的广泛遗传学研究）将利用成像遗传学这一新兴领域，对强迫症的谷氨酸假说进行关键测试。Rosenberg小组的初步研究（R01MH59299, K24MH02037）表明，谷氨酸能介导的丘脑皮质纹状体功能障碍可能是儿童强迫症的病理生理标志。Hanna （R01MH53876, K20MH01065）、Arnold和Kennedy小组的独立研究结果表明，谷氨酸转运体基因SLC1A1和谷氨酸受体基因GRIN2B与早发性强迫症有显著关联。基于这三个位点之间长期存在的合作，在儿科强迫症患者中令人兴奋的新试点数据表明，大脑区域谷氨酸能浓度（特别是前扣带）与GRIN2B-rs1019385多态性之间存在显著关联。在强迫症患者中，发现了GRIN2B rs1805476变异与增加的左眶额和增加的前扣带体积（r> L）显著相关，而不是右眶额和增加的前扣带体积（r1805476）。GRIN2B-rs1019385变异显示出与左侧尾状核体积减小而非右侧尾状核体积减小相关的非显著趋势。SLC1A1 rs3056-AA基因型与左右丘脑体积增加显著相关。因此，GRIN2B和SLC1A1序列变异可能与与强迫症发病机制有关的脑区域内的体积和谷氨酸能浓度差异有关。高场（3特斯拉）质子磁共振波谱（1H MRS）可以独特地区分谷氨酸能共振的亚组分（谷氨酸和谷氨酰胺），也可以测量其他化合物，包括假定的神经元标记物、n -乙酰-天冬氨酸、胆碱化合物和肌酸。在韦恩州立大学密歇根儿童医院的3T靶向1H MRS和体积成像将结合编码GRIN2B和SLC1A1基因的37个多态性的基因分型（多伦多大学），以检查这些变异对200名7-19岁儿童强迫症患者的丘脑皮质纹状体回路的影响，以及200名年龄和性别匹配的健康对照。结合生物学、遗传和行为/症状变量的研究，呼吁在PA-07- 092中概述的精神疾病的转化方法，精神障碍临床和服务研究的协作R01s，这可能会导致更好地理解儿科强迫症，反过来，新的诊断和治疗方法。公共卫生相关性：强迫症（OCD）是一种慢性致残障碍，每年造成的经济损失超过20亿美元，影响到美国大约100万儿童和青少年，使其成为一个重大的公共卫生问题。为了提高我们诊断、治疗和预防这种疾病的能力，迫切需要研究这种疾病的生物学原理。通过结合脑成像和遗传学，就像我们在这个提议中所做的那样，我们可以更好地了解儿童强迫症的生物学，进而开发出更有效的治疗方法来治疗这种严重的儿童精神病理。

DESCRIPTION (provided by applicant): This is a competitive renewal application of the Wayne State Principal Investigator's (Rosenberg) grant award, R01MH59299. Obsessive compulsive disorder (OCD) is a severe, prevalent, and chronically disabling disorder that emerges during childhood in as many as 50% of all cases. The overall goal of this project, which combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites - Wayne State (neuroimaging of pediatric OCD), University of Michigan (family and molecular genetic studies of early-onset OCD) and University of Toronto (extensive genetic studies of glutamate receptor and transporter genes in OCD) - is to exploit the emerging field of imaging genetics in a critical test of the glutamate hypothesis of OCD. Preliminary studies from Rosenberg's group (R01MH59299, K24MH02037) suggest that a glutamatergically-mediated thalamocortical-striatal dysfunction may serve as a pathophysiological marker in pediatric OCD. Independent findings by the Hanna (R01MH53876, K20MH01065) and the Arnold and Kennedy groups demonstrate a significant association of the glutamate transporter gene, SLC1A1, and glutamate receptor gene, GRIN2B, with early-onset OCD. Building on long-standing existing collaborations among the three sites, exciting new pilot data in pediatric OCD patients demonstrates a significant association between regional brain glutamatergic concentrations, particularly in the anterior cingulate and the GRIN2B-rs1019385 polymorphism. Significant associations between increased left, but not right orbital frontal and increased anterior cingulate volume (R>L) with the rs1805476 variant of GRIN2B were identified in OCD patients. The GRIN2B-rs1019385 variant exhibited a non-significant trend towards association with decreased left but not right caudate volume. The SLC1A1 rs3056-AA genotype was significantly associated with increased right and left thalamic volume. Thus, GRIN2B and SLC1A1 sequence variations may be associated with differences in volume and glutamatergic concentrations within brain regions implicated in the pathogenesis of OCD. High field (3 Tesla) proton magnetic resonance spectroscopy (1H MRS) can uniquely distinguish the subcomponents of the glutamatergic resonance (glutamate and glutamine), as well as measure other compounds including the putative neuronal marker, N-acetyl-aspartate, choline compounds and creatine. Targeted 1H MRS and volumetric imaging at 3T at the Children's Hospital of Michigan at Wayne State will be combined with genotyping of 37 polymorphisms in the genes encoding GRIN2B and SLC1A1 (University of Toronto) to examine the effects of these variants on thalamocortical-striatal circuitry in 200 pediatric OCD patients, 7-19 years, and 200 age and sex-matched healthy controls. The combined study of biological, genetic and behavioral/symptom variables enacts the call for translational approaches to mental illness outlined in PA-07- 092, Collaborative R01s for Clinical and Services Studies of Mental Disorders, which may lead to a better understanding of pediatric OCD and, in turn, to new diagnostic and treatment approaches. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is a chronic and disabling disorder that costs the economy over $2 billion annually and affects approximately one million children and adolescents in the United States, making it a significant public health problem. There is a pressing need for studies that shed light on the biology of the disorder in order to improve our ability to diagnose, treat, and prevent the disorder. By combining brain imaging and genetics, as we do in this proposal, we can better understand the biology of pediatric OCD and, in turn, develop more effective treatments for this severe form of childhood psychopathology.