3/3-Brain Chemistry and Genetics in Pediatric OCD

描述(由申请人提供)：这是韦恩州立大学首席调查员(罗森伯格)奖励奖的竞争性续签申请，R01MH59299。强迫症(OCD)是一种严重、普遍和长期致残的疾病，在儿童时期出现的比例高达50%。这个项目结合了三个绩效网站的独特临床评估、磁共振成像和遗传学专业知识-韦恩州立大学(儿童强迫症的神经成像)、密歇根大学(早发性强迫症的家庭和分子遗传学研究)和多伦多大学(对强迫症谷氨酸受体和转运体基因的广泛遗传学研究)-是在对强迫症谷氨酸假说的关键测试中利用成像遗传学这一新兴领域。Rosenberg的研究小组(R01MH59299，K24MH02037)的初步研究表明，谷氨酸介导的丘脑皮质-纹状体功能障碍可能是儿童强迫症的一个病理生理标志。Hanna(R01MH53876，K20MH01065)以及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与早发性强迫症显著相关。建立在这三个地点之间长期存在的合作的基础上，令人兴奋的新的试点数据在儿童强迫症患者中证明了区域大脑谷氨酸能浓度之间的显著关联，特别是在前扣带回和GRIN2B-rs1019385多态之间。在强迫症患者中，发现左侧而不是右侧眼眶额叶的增大和前扣带回体积的增大(R&GT；L)与GRIN2B的rs1805476变异显著相关。GRIN2B-rs1019385变异表现出与左侧尾状核体积减少而不是右侧尾状核体积减少相关的非显著趋势。SLC1A1 rs3056-AA基因型与左右丘脑体积增大显著相关。因此，GRIN2B和SLC1A1序列变异可能与与强迫症发病有关的脑区体积和谷氨酸浓度的差异有关。高场(3特斯拉)质子磁共振波谱(1HMRS)可以唯一地区分谷氨酸能共振的亚组分(谷氨酸和谷氨酰胺)，还可以测量其他化合物，包括可能的神经元标记物N-乙酰天冬氨酸、胆碱化合物和肌酸。韦恩州立大学密歇根儿童医院的定向1H MRS和3T体积成像将与编码GRIN2B和SLC1A1(多伦多大学)的基因的37个多态基因分型相结合，在200名7-19岁的儿童强迫症患者和200名年龄和性别匹配的健康对照中检查这些变异对丘脑皮质-纹状体回路的影响。对生物、遗传和行为/症状变量的综合研究制定了PA-07-092中概述的精神疾病的翻译方法的呼吁，这可能会导致对儿童强迫症的更好理解，进而导致新的诊断和治疗方法。公共卫生相关性：强迫症(OCD)是一种慢性致残性疾病，每年造成超过20亿美元的经济损失，影响美国约100万儿童和青少年，使其成为一个重大的公共卫生问题。迫切需要对这种疾病的生物学进行研究，以提高我们诊断、治疗和预防这种疾病的能力。通过将脑成像和遗传学相结合，就像我们在这项提案中所做的那样，我们可以更好地了解儿童强迫症的生物学，进而为这种严重的儿童精神病理学开发更有效的治疗方法。

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.