Deconstructing the Smoking and ADHD Comorbidity: A Multilevel Genetic Approach

项目摘要 这个K23奖项推进了候选人整合药物遗传学和精神病学的长期目标 吸烟/尼古丁依赖（ND）及其与注意力共现研究的遗传学方法 缺陷多动障碍（ADHD）。拟议的培训将使PI能够发展所需的技能， 在这一领域的独立跨学科研究生涯。青少年吸烟行为的风险， 包括早期开始吸烟的年龄和经常吸烟的可能性，与临床 ADHD的诊断和ADHD症状的非临床水平。几条趋同的工作路线表明， 在ADHD症状存在的高吸烟率可能与共同的遗传有关 增加ND和ADHD风险的漏洞。此外，吸烟的风险增加， 尼古丁和尼古丁戒断对ADHD相关缺陷的影响可能与吸烟有关。 执行功能（EF）和延迟折扣（DD）。研究计划的重点是阐明一个 通过检查青少年吸烟的遗传和认知相关性来研究神经生物学途径 注意力缺陷多动症首先，将对现存的遗传信息样本进行二次分析， 文献中的空白涉及1）潜在的遗传、环境和基因受环境影响的作用 吸烟/ND和ADHD之间的重叠，以及2）与测量的遗传变异相关的关联， 尼古丁的神经药理学（即多巴胺能、烟碱乙酰胆碱能和尼古丁代谢 基因）和ND/ADHD共病。很少有遗传学研究同时检查ADHD和吸烟 这项工作将有助于表征表型，并选择最相关的测量基因， 这一病因学途径，即青少年吸烟中存在ADHD症状。二是新 将使用实验室药理学方法收集数据，以探索认知和遗传机制。 通过评估尼古丁的影响，发现ADHD青少年吸烟的潜在风险增加 有和没有ADHD的青少年吸烟者的EF和DD戒烟。EF和DD性能将 在经过24小时生化验证后，对患有（n=32）和未患有（n=32）ADHD的青少年吸烟者进行比较 在以下条件下戒烟：1）安慰剂贴剂（尼古丁戒烟）和2）14 mg尼古丁 尼古丁替代品（尼古丁替代品）还将收集DNA，以测试遗传因素的调节作用。 与尼古丁神经药理学有关的EF和DD过程的变化。结果将告知关键的 在高风险人群中使用尼古丁的脆弱性，即患有ADHD的青少年，并推进 更广泛地了解ND的致病因素。这项研究将导致随后的赠款 应用于进一步探索与吸烟风险相关的遗传和神经药理学机制， ADHD的存在以及临床项目，以制定更有效的干预措施，为ND在这个高- 风险组。为了使PI能够追求这一长期的研究议程，她将与经验丰富的导师合作 以她目前在ADHD神经认知表型方面的专业知识为基础，进行五个方面的培训：（1） 尼古丁精神药理学，2）行为药理学实验室方法，3） 青少年吸烟研究，4）行为遗传分析方法，5）综合这些培训 将这些经验纳入ND的长期药物遗传学研究计划。综合考虑， 研究和培训计划的重点是整合遗传学和药理学方法， 提高对ND病因和治疗因素的认识，并为PI做好充分准备， 在该领域的独立临床研究生涯。

Project Summary This K23 award advances the Candidate's long term goal of integrating pharmacogenetic and psychiatric genetic approaches in the study of smoking/nicotine dependence (ND) and its co-occurrence with Attention Deficit Hyperactivity Disorder (ADHD). The proposed training will enable the PI to develop the skills needed for an independent interdisiplinary research career in this field. Risk for smoking behaviors in adolescents, including earlier age of initiation and likelihood of regular smoking, has been associated with both a clinical diagnosis of ADHD and non-clinical levels of ADHD symptoms. Several converging lines of work suggest that the high rates of smoking in the presence of ADHD symptoms may be related to common genetic vulnerabilities that increase risk for both ND and ADHD. In addition, increased risk for smoking in this population may be related to the effects of nicotine and nicotine abstinence on ADHD-related deficits in executive function (EF) and delay discounting (DD). The research plan focuses on elucidating a neurobiological pathway to ND by examining the genetic and cognitive correlates of smoking in adolescents with ADHD. First, secondary analysis of extant geneticially-informative samples will be conducted to address gaps in the literature related to 1) the latent genetic, environmental, and gene by environmental influences on the overlap between smoking/ND and ADHD and 2) associations with measured genetic variation related to the neuropharmacology of nicotine (i.e. dopaminergic, nicotinic acetylcholinergic, and nicotine metabolism genes) and the ND/ADHD comorbidity. Few genetic studies have examined ADHD and smoking concurrently and this work will assist in characterizing phenotypes and selecting measured genes most relevant to this etiological pathway, that is, adolescent smoking in the presence of ADHD symptoms. Second, new data will be collected using laboratory pharmacology methods to probe the cognitive and genetic mechanisms underlying increased risk for smoking in adolescents with ADHD by assessing the effects of nicotine abstinence on EF and DD in adolescent smokers with and without ADHD. EF and DD performance will be compared in adolescent smokers with (n=32) and without (n=32) ADHD after 24-hour biochemically verified smoking abstinence in the following conditions: 1) placebo patch (nicotine abstinence) and 2) 14 mg nicotine patch (nicotine replacement). DNA will also be collected in order to test the moderating role of genetic variation related to nicotine neuropharmacology on EF and DD processes. Results will inform a critical vulnerability for nicotine use in a high risk population, i.e. adolescents with ADHD, and advance the understanding of etiological factors in ND more broadly. This research will lead to subsequent grant applications to further probe genetic and neuropharmacological mechanisms associated with smoking risk in the presence of ADHD as well as clinical projects to develop more effective interventions for ND in this high- risk group. To enable the PI to pursue this long-term research agenda, she will work with experienced mentors to build upon her current expertise in neurocognitive phenotypes of ADHD with five areas of training: (1) nicotine psychopharmacology, 2) laboratory methods in behavioral pharmacology, 3) special issues in adolescent smoking research, 4) behavioral genetic analytic approaches, and 5) synthesizing these training experiences into a long-term pharmacogenetics of ND research program. Taken together, the proposed research and training plans address a key priority of integrating genetic and pharmacological methodologies to advance the understanding of etiological and treatment factors in ND, and it will fully prepare the PI for an independent clinical research career in the field.