Deconstructing the Smoking and ADHD Comorbidity: A Multilevel Genetic Approach

描述（由申请人提供）：该K23奖项推进了候选人的长期目标，即在吸烟/尼古丁依赖（ND）及其与注意缺陷多动障碍（ADHD）的共同发生的研究中整合药物遗传学和精神病学遗传学方法。拟议的培训将使PI发展在这一领域的独立跨学科研究生涯所需的技能。青少年吸烟行为的风险，包括开始吸烟的年龄和经常吸烟的可能性，与ADHD的临床诊断和ADHD症状的非临床水平有关。几项趋同的研究表明，在ADHD症状存在的情况下吸烟率高可能与增加ND和ADHD风险的常见遗传脆弱性有关。此外，该人群吸烟风险增加可能与尼古丁和尼古丁戒断对ADHD相关执行功能（EF）和延迟折扣（DD）缺陷的影响有关。该研究计划的重点是通过检查ADHD青少年吸烟的遗传和认知相关性来阐明ND的神经生物学途径。首先，将对现有遗传信息样本进行二次分析，以解决文献中与以下方面相关的空白：1）潜在遗传、环境和基因对吸烟/ND和ADHD之间重叠的影响，以及2）与尼古丁神经药理学相关的测量遗传变异的相关性（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。这项工作将有助于表征与青少年吸烟遗传研究最相关的表型，特别是在存在ADHD症状的情况下，并选择特定于此病因途径的测量基因。其次，将使用实验室药理学方法收集新数据，通过评估尼古丁戒断对伴和不伴ADHD的青少年吸烟者EF和DD的影响，探索ADHD青少年吸烟风险增加的认知和遗传机制。在以下条件下，在经生化验证戒烟24小时后，将在患有（n=32）和不患有（n=32）ADHD的青少年吸烟者中比较EF和DD性能：1）安慰剂贴剂（尼古丁戒烟）和2）14 mg尼古丁贴剂（尼古丁替代）。还将采集DNA，以检测与尼古丁神经药理学相关的遗传变异对EF和DD过程的调节作用。结果将告知高危人群（即ADHD青少年）使用尼古丁的关键脆弱性，并更广泛地促进对ND病因因素的理解。这项研究将导致随后的拨款申请，以进一步探索与ADHD存在下吸烟风险相关的遗传和神经药理学机制，以及临床项目，以开发更有效的ND干预措施。为了使PI能够进行这一长期的研究议程，她将与经验丰富的导师合作，利用她目前在ADHD神经认知表型方面的专业知识，进行五个领域的培训：（1）尼古丁精神药理学，2）行为药理学实验室方法，3）青少年吸烟现象学，4）高级行为遗传分析方法，5）ND药物遗传学。总而言之，拟议的研究和培训计划解决了整合遗传学和药理学方法的关键优先事项，以促进对ND病因和治疗因素的了解，并将为PI在该领域的独立临床研究生涯做好充分准备。

DESCRIPTION (provided by applicant): 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 interdisciplinary 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 genetically-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. This work will assist in characterizing phenotypes most relevant to genetic studies of adolescent smoking, especially in the presence of ADHD symptoms, and in selecting measured genes specific to this etiological pathway. 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 neuro-pharmacology 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) phenomenology of adolescent smoking, 4) advanced behavioral genetic analytic approaches, and 5) pharmacogenetics of ND. 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.