Genetic Imaging of Working Memory and Interference Control in ADHD

ADHD 工作记忆的基因成像和干扰控制

• 批准号: 8336815
• 负责人: ALYSA E DOYLE
• 金额: $ 26.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8336815
• 关键词: Adopted; Adult; Animal Model; Attention deficit hyperactivity disorder; Behavior; Behavioral Genetics; Behavioral Symptoms; Biological Neural Networks; Brain; Candidate Disease Gene; Catecholamines; Clinical; Cognition; Cognition Disorders; Corpus striatum structure; DRD4 gene; Data; Data Set; Diagnostic tests; Dimensions; Disease; Disease model; Dopamine; Early treatment; Equation; Functional disorder; General Hospitals; Genes; Genetic; Genetic Variation; Goals; Heritability; Hyperactive behavior; Image; Impaired cognition; Impulsivity; Individual; Investigation; Knowledge; Lead; Light; Link; Literature; Measures; Mediating; Meta-Analysis; Modeling; Molecular Genetics; Neurobiology; Neurocognition; Neurocognitive; Outcome; Pathway interactions; Performance; Pharmacological Treatment; Phenotype; Prevalence; Prevention; Process; Public Health; Regulation; Reporting; Research Project Grants; Resources; Risk; S-nitro-N-acetylpenicillamine; Sampling; Short-Term Memory; Structure; Susceptibility Gene; Symptoms; Testing; Therapeutic; Variant; Work; base; cognitive function; cost; cost effective; endophenotype; executive function; genome wide association study; genome-wide; heuristics; improved; inattention; indexing; innovation; interest; neuroimaging; neurotransmission; new therapeutic target; trait; volunteer

DESCRIPTION (provided by applicant): Several genes related to the neurotransmission of dopamine, including DRD4, SLC6A3 and SNAP-25, have been associated with ADHD via meta-analyses and animal models. Yet, little is known about how these genes act on the brain to produce meaningful phenotypic variation in individuals with and without the disorder. Because performance on measures of working memory and interference control is impaired in ADHD samples, familially-linked to the condition and impacted by dopamine function, genetic imaging studies investigating neural networks that support these executive functions are likely to offer further clarification of etiological pathways. The overarching aim of the current project is to use an existing data set to generate hypotheses about the relationship between three ADHD candidate genes (DRD4, SLC6A3 and SNAP-25), neuroimaging measures of working memory and interference control networks, neurocognitive measures of these functions and behavioral symptoms of ADHD. Our specific aims involve 1) examining the association between polymorphic variation across these candidate genes and ADHD neuroimaging phenotypes, 2) including neurocognitive measures in multivariate association tests of neuroimaging phenotypes and these genes, and 3) exploring the relationship of positively associated phenotypes using structural equation models to better understand risk mechanisms that link genes and brain function to cognition and disorder. Subjects are individuals with (N =128) and without (N =68) ADHD who have had genetic, functional and structural neuroimaging, neurocognitive and ADHD symptom data collected as part of other research projects at Mass General Hospital. By exploring genetic, neuroimaging, neurocognitive and symptom data simultaneously in an existing sample, we will generate testable models of pathways from genes to behavior in a comprehensive, cost-efficient and timely manner. This work will lead to improved understanding of the heritable pathophysiology and risk mechanisms underlying ADHD and impaired cognition, which in turn should create new opportunities for prevention, early intervention, therapeutics and diagnostic tests.

描述（由申请人提供）：几个与多巴胺神经传递相关的基因，包括DRD4， SLC6A3和SNAP-25，通过meta分析和动物模型与ADHD相关。然而，对于这些基因如何作用于大脑，在患有和不患有这种疾病的个体中产生有意义的表型变异，人们知之甚少。由于ADHD样本在工作记忆和干扰控制方面的表现受损，与这种情况有家族关系，并受到多巴胺功能的影响，因此研究支持这些执行功能的神经网络的遗传成像研究可能会进一步阐明病因途径。当前项目的总体目标是使用现有的数据集来产生关于三个ADHD候选基因（DRD4， SLC6A3和SNAP-25），工作记忆和干扰控制网络的神经影像学测量，这些功能的神经认知测量和ADHD行为症状之间关系的假设。我们的具体目标包括1)检查这些候选基因的多态性变异与ADHD神经影像学表型之间的关联，2)包括神经影像学表型与这些基因的多变量关联测试中的神经认知测量，以及3)使用结构方程模型探索正相关表型的关系，以更好地了解将基因和脑功能与认知和障碍联系起来的风险机制。研究对象是有（N =128）和没有（N =68）多动症的个体，他们有遗传、功能和结构神经影像学、神经认知和多动症症状数据，这些数据是麻省总医院其他研究项目的一部分。通过在现有样本中同时探索遗传、神经影像学、神经认知和症状数据，我们将以全面、经济、及时的方式生成从基因到行为途径的可测试模型。这项工作将有助于提高对ADHD和认知障碍的遗传病理生理和风险机制的理解，从而为预防、早期干预、治疗和诊断测试创造新的机会。