Tourette Syndrome genetics and neuroimaging international collaborative study

抽动秽语综合症遗传学和神经影像学国际合作研究

• 批准号: 10583548
• 负责人: Peristera Paschou
• 金额: $ 49.11万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583548
• 关键词: Address; Affect; Agreement; Anxiety Disorders; Attention deficit hyperactivity disorder; Behavioral; Biological Markers; Black race; Brain; Brain imaging; Brain region; Categories; Child; Clinical; Clinical Data; Collaborations; Complex; Country; Data; Data Analyses; Data Set; Databases; Development; Diagnostic; Disease; Environmental Risk Factor; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Future; Generations; Genetic; Genetic Risk; Genetic study; Genomics; Gilles de la Tourette syndrome; Goals; Heterogeneity; Hispanic; Impairment; Individual; Infrastructure; International; Lead; Light; Magnetic Resonance Imaging; Maintenance; Major Depressive Disorder; Maps; Mental disorders; Meta-Analysis; Motor Tics; Neurobiology; Obsessive-Compulsive Disorder; Participant; Pathway interactions; Patients; Phenotype; Play; Population Heterogeneity; Publishing; Quality Control; Quality of life; Reproducibility; Research Personnel; Resources; Role; Sample Size; Sampling; Site; Standardization; Structure; Testing; Vocal Tics; analysis pipeline; autism spectrum disorder; biobank; biomarker identification; biomarker validation; cohort; comorbidity; gene interaction; genetic association; genetic information; genome wide association study; genomic locus; improved; individual patient; individualized medicine; neuroimaging; neuropsychiatric disorder; novel; outcome prediction; personalized management; population based; portability; psychiatric genomics; recruit; risk variant; structural imaging; success; working group

Tourette Syndrome (TS) is characterized by multiple, persistent motor and vocal tics and affects approximately 1% of children worldwide. There is no cure for TS and efforts to develop novel treatments are hampered by our limited understanding of the underlying neurobiology and brain structural and functional deficits. Although tics represent the hallmark feature of TS, up to 90% of patients present with additional neuropsychiatric disorders, including Obsessive Compulsive Disorder (OCD up to 50% of TS patients), Attention Deficit Hyperactivity Disorder (ADHD up to 54.3%), Autism Spectrum Disorders (ASD up to 20%), Major Depressive Disorder (MDD up to 26%), and Anxiety Disorders (AXD up to 36%). These comorbidities contribute to decreased quality of life and introduce etiological and phenotypic heterogeneity that further hampers efforts to elucidate the TS neurobiology. Here, we are proposing to investigate TS-related brain structure and function at a large scale but also to identify those factors that lead to high comorbidity with other disorders. Motivated by international collaborative studies on the genetics and neuroimaging of TS led by the PI, we bring together all major worldwide collaborative efforts on neuroimaging and genetics for TS and aim to integrate with equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. We take advantage of access to data, resources and standardized pipelines from the ENIGMA (Enhancing Neuroimaging Genetics through Meta- Analysis) consortium and the Psychiatric Genomics Consortium (PGC). First, we will establish the ENIGMA-TS working group, for which PI Paschou has already laid the groundwork, with 17 sites from nine countries having agreed to contribute existing neuroimaging and clinical data from 1,930 cases and controls. We will pool together T1 structural imaging data as well as rsfMRI and DTI data. Second, we will pursue the largest neuroimaging studies for TS to date aiming to understand the pathophysiology of the disorder. Pursuing cross-disorder analysis, we will also integrate our TS neuroimaging data with existing ENIGMA data for the most frequently comorbid disorders in TS (OCD, ADHD, ASD, MDD, and AXD). Third, we will aim to uncover brain regions that correlate to genetic background in TS and related disorders. To do this we will analyze TS genomewide association studies (GWAS) but also pursue cross-disorder GWAS for TS and comorbid disorders. We will leverage our findings from the first large-scale cross-disorder GWAS meta-analysis for TS, OCD, ADHD, ASD (led by the PI), as well as access to data from ENIGMA GWAS on brain structure from more than 50,000 individuals and the UK Biobank on additional 10,000 individuals. Importantly, we will also leverage access to population-based cohorts (ABCD and Generation R), with longitudinal brain imaging, clinical but also genetic information in order to replicate our findings to diverse populations and explore correlations to behavioural profiles moving beyond strict diagnostic categories. Ultimately, our findings will help elucidate brain structure and function in TS but also disentangle relationships with comorbid OCD, ADHD, ASD, MDD, and AXD.

抽动秽语综合征（TS）的特征是多发性、持续性运动和发声抽搐， 全世界1%的儿童。TS没有治愈方法，开发新疗法的努力受到我们的限制。 对潜在的神经生物学和大脑结构和功能缺陷的理解有限。虽然tics 代表TS的标志性特征，高达90%的患者存在其他神经精神疾病， 包括强迫症（强迫症高达50%的TS患者），注意力缺陷多动症 障碍（ADHD高达54.3%），自闭症谱系障碍（ASD高达20%），重度抑郁症（MDD 焦虑症（AXD）高达36%。这些合并症导致生活质量下降 并引入病因学和表型异质性，进一步阻碍了阐明TS的努力 神经生物学在这里，我们建议大规模研究与TS相关的大脑结构和功能， 也要确定那些导致与其他疾病的高共病率的因素。受国际 由PI领导的TS遗传学和神经影像学合作研究，我们汇集了全球所有主要研究 在TS的神经成像和遗传学方面的合作努力，旨在与同等规模的，已经 现有的研究高度共病强迫症，多动症，ASD，MDD和AXD。We take advantage优势of access访问to data数据， ENIGMA的资源和标准化管道（通过Meta增强神经成像遗传学） 分析）联盟和精神病基因组学联盟（PGC）。首先，我们将建立ENIGMA-TS 工作组，PI Paschou已经为之奠定了基础，来自9个国家的17个网站已经 同意贡献来自1,930例病例和对照的现有神经影像学和临床数据。我们会凑在一起 T1结构成像数据以及rsfMRI和DTI数据。第二，我们将进行最大的神经成像， 迄今为止，旨在了解该疾病的病理生理学的TS研究。追求交叉无序 我们还将把TS神经成像数据与现有的ENIGMA数据进行整合， TS中的共病疾病（OCD、ADHD、ASD、MDD和AXD）。第三，我们的目标是揭示大脑区域， 与TS和相关疾病的遗传背景相关。为此，我们将分析TS全基因组 关联研究（GWAS），但也追求交叉疾病GWAS TS和共病疾病。我们将 利用我们对TS、OCD、ADHD、ASD的首次大规模交叉障碍GWAS荟萃分析的发现， (led由PI），以及访问来自ENIGMA GWAS的关于大脑结构的数据， 个人和英国生物银行对额外的10,000人。重要的是，我们还将利用 基于人群的队列（ABCD和R代），纵向脑成像，临床和遗传 为了将我们的发现复制到不同的人群中，并探索与行为的相关性， 超越了严格的诊断类别。最终，我们的发现将有助于阐明大脑结构， 在TS中发挥作用，但也解开了与共病强迫症，多动症，ASD，MDD和AXD的关系。