Genetics of Executive Functions in ADHD & Non-ADHD

描述(由申请者提供)：这是一份临床科学家发展导师奖的申请书。这位候选人提出了一项研究计划，旨在研究患有和不患有注意力缺陷多动障碍(ADFID)的家庭执行功能的遗传学。这项研究的目标是1)整合应聘者在发展神经心理学、行为遗传学和破坏性行为障碍方面的知识，2)帮助她在分子遗传学领域发展新的方法论和生物统计学技能。 虽然家庭、双胞胎和收养研究表明ADHD是一种具有强大遗传成分的家族性疾病，但ADFID表型的复杂性阻碍了对参与该疾病发病机制的特定基因的识别。由于ADHD与执行功能缺陷有关，而且遗传和神经心理学研究都表明多巴胺通路与这种疾病的病理生理学有关，因此目前的项目将使用执行功能的测量方法来创建精致的ADHD表型(即家族亚型和/或内表型)，然后将在候选多巴胺基因的关联和连锁研究中进行检查。这个项目代表了第一个关于ADHD的程序性工作，从临床定义的表型转移到与大脑功能更直接相关的表型。 研究计划：由于行政职能分类的不确定性，行政职能的各种业务定义将从经验和概念上推导出来。将检查这些定义的熟悉性、进程、稳定性以及与功能损害和外部相关因素的关系。然后，将使用定义来表征ADHD在DSM-IV亚型、性别、发育和共患方面的潜在神经心理异质性。基于上述发现，在多个家庭中，相对风险比和成员预测将确定执行功能的量化和分类表型以及神经心理受损的ADHD亚组，这将增强后续连锁和关联研究的力量。最后，这些优化的表型将接受连锁分析和基于家系和基因组控制的关联分析。需要研究的候选基因是DRD4、DAT和DRD5，因为它们与ADHD具有神经生物学相关性，而且现有关联研究的荟萃分析表明，它们参与了ADHD的易感性。 职业发展计划：培训将强调进行复杂表型的分子遗传学研究所必需的方法学和生物统计学技能。哈佛大学公共卫生学院和洛克菲勒大学将开设统计遗传学和遗传分析软件使用方面的课程。专家顾问的指导和监督将侧重于表型定义、遗传流行病学和统计遗传学。这一培训将使候选人成为一名独立的研究人员，能够在神经心理学、遗传学和发展精神病理学方面开展跨学科的工作。

DESCRIPTION (provided by applicant): This is an application for a Mentored Clinical Scientist Development Award. The candidate is proposing a program of research that examines the genetics of executive functions in families with and without attention deficit hyperactivity disorder (ADFID). The goals of this research are 1) to integrate the candidate's knowledge of developmental neuropsychology, behavioral genetics and disruptive behavior disorders and 2) to help her develop new methodological and biostatistical skills in the domain of molecular genetics. Although family, twin and adoption studies indicate that ADHD is a familial condition with a robust genetic component, the complexity of the ADFID phenotype has impeded the identification 01 the specific genes involved in the pathogenesis of this condition. Because ADHD is associated with executive function deficits, and because both genetic and neuropsychological studies implicate dopamine pathways in the pathophysiology of this disorder, the current project will use measures of executive functions to create refined ADHD phenotypes (i.e. familial subtypes and/or endophenotypes) that will then be examined in association and linkage studies of candidate dopamine genes. This project represents the first programmatic work on ADHD that moves from clinically defined phenotypes to phenotypes that are more directly linked to brain function. Research Plan: Because of uncertainties in the taxonomy of executive functions, various operational definitions of executive functions will be empirically and conceptually derived. These definitions will be examined for familiality, course, stability and relationship to functional impairment and external correlates. Definitions will then be used to characterize potential neuropsychological heterogeneity in ADHD across DSM-IV subtypes, gender, development and comobidities. Based on the above findings, relative risk ratios and prediction of membership in multiplex families will identify the quantitative and categorical executive function phenotypes and neuropsychologically impaired ADHD subgroups that would enhance the power of subsequent linkage and association studies. Finally, these optimized phenotypes will be subjected to linkage analysis and family-based and genomic-control association analyses. Candidate genes to be examined are DRD4, DAT and DRD5 because of their neurobiologic relevance to ADHD and because meta-analyses of extant association studies suggest that they mediate susceptibility to this condition. Career Development Plan: Training will emphasize the methodological and biostatistical skills necessary for conducting molecular genetics studies of complex phenotypes. Courses will be taken in statistical genetics and the use of software for genetic analyses at the Harvard School of Public Health and Rockefeller University. Tutorials and supervision by expert consultants will focus on phenotype definition, genetic epidemiology and statistical genetics. This training will prepare the candidate to be an independent researcher who can conduct interdisciplinary work on neuropsychology, genetics and developmental psychopathology.