Genetic Imaging of Working Memory and Interference Control in ADHD

描述(申请人提供)：几个与多巴胺神经传递有关的基因，包括DRD4、SLC6A3和SNAP-25，通过荟萃分析和动物模型被认为与ADHD有关。然而，关于这些基因如何作用于大脑，从而在患有和不患有这种疾病的个体中产生有意义的表型差异，人们知之甚少。由于ADHD样本在测量工作记忆和干扰控制方面的表现受到损害，与这种情况密切相关，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基因成像研究可能会进一步澄清病因途径。当前项目的总体目标是使用现有的数据集来生成关于三个ADHD候选基因(DRD4、SLC6A3和SNAP-25)之间的关系的假设、工作记忆和干扰控制网络的神经成像指标、这些功能的神经认知指标以及ADHD的行为症状。我们的具体目标包括1)检查这些候选基因的多态变异与ADHD神经成像表型之间的关联，2)在神经成像表型与这些基因的多变量关联测试中包括神经认知测量，以及3)使用结构方程模型探索正相关表型的关系，以更好地理解将基因和大脑功能与认知和障碍联系起来的风险机制。受试者是患有ADHD(N=128)和没有ADHD(N=68)的个体，他们在马萨诸塞州综合医院的其他研究项目中收集了遗传、功能和结构神经成像、神经认知和ADHD症状数据。通过在现有样本中同时探索遗传、神经成像、神经认知和症状数据，我们将以全面、经济高效和及时的方式生成从基因到行为的可测试路径模型。这项工作将有助于更好地理解ADHD和认知受损背后的可遗传病理生理学和风险机制，这反过来将为预防、早期干预、治疗和诊断测试创造新的机会。 公共卫生相关性：通过荟萃分析和动物模型，DRD4、SLC6A3和SNAP-25与ADHD有关；然而，这些基因导致神经认知和行为变化的机制尚不清楚。基于结构和功能神经成像的工作记忆和干扰控制网络的测量是可能的内在表型，可能揭示与这些基因相关的风险机制。该项目将研究这些基因、神经成像和神经认知测量与患有和不患有ADHD症状的个体之间的关系。我们的目标是生成关于从基因到大脑再到行为的路径的假设。提高对ADHD的可遗传病理生理学和导致认知功能低下的遗传介导的神经发育风险机制的理解，具有重要的临床和公共卫生意义。这些知识可以为治疗学和诊断测试发现新的目标，并有助于将有限的社会资源集中在那些有ADHD或认知障碍风险的人身上。

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. PUBLIC HEALTH RELEVANCE: DRD4, SLC6A3 and SNAP-25 have been associated with ADHD via meta-analysis and animal models; however, the mechanism by which these genes contribute to variation in neurocognition and behavior is unknown. Structural and functional neuroimaging-based measures of working memory and interference control networks are putative endophenotypes that may shed light on the risk mechanisms associated with these genes. This project will examine the relationship between these genes, neuroimaging and neurocognition measures and ADHD symptoms in individuals with and without the disorder. Our goal is to generate hypotheses regarding pathways from genes to brain to behavior. Improved understanding of the heritable pathophysiology of ADHD and the genetically-mediated neurodevelopmental risk mechanisms that lead to poor cognitive function have important clinical and public health implications. Such knowledge could uncover new targets for therapeutics and diagnostic tests and help focus limited societal resources on those at risk for ADHD or cognitive impairment.