Deconstructing the Smoking and ADHD Comorbidity: A Multilevel Genetic Approach

解构吸烟和多动症合并症：多层次遗传学方法

• 批准号: 8911909
• 负责人: L. Cinnamon Bidwell
• 金额: $ 16.08万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911909
• 关键词: Abstinence; Accounting; Address; Adolescent; Age; Applications Grants; Architecture; Area; Attention deficit hyperactivity disorder; Behavioral Genetics; Caucasians; Caucasoid Race; Cessation of life; Cigarette; Clinical; Clinical Research; Cognitive; Cognitive deficits; Comorbidity; DNA; DSM-IV; Data; Data Analyses; Data Collection; Dimensions; Environment; Future; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Goals; Heterogeneity; Hour; Investigation; Laboratories; Lead; Literature; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolism; Methodology; Methods; Neurobiology; Neurocognitive; Neuropharmacology; Nicotine; Nicotine Dependence; Not Hispanic or Latino; Pathway interactions; Performance; Pharmacogenetics; Pharmacology; Phenotype; Physiological; Placebos; Population; Prevention program; Process; Psychopharmacology; Public Health; Reaction; Research; Research Training; Risk; Role; Sampling; Series; Smoke; Smoker; Smoking; Smoking Behavior; Structure; Symptoms; Testing; Training; Treatment Factor; Twin Multiple Birth; Variant; Work; adolescent smoking; behavioral pharmacology; career; clinical Diagnosis; design; discounting; effective intervention; executive function; experience; genetic association; genetic risk factor; high risk; improved; inattention; nicotine patch; nicotine replacement; programs; psychogenetics; skills; treatment program

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.

项目概要 该 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）及其与注意力共存研究中的遗传学方法 缺陷多动障碍（ADHD）。拟议的培训将使 PI 能够培养以下方面所需的技能： 该领域的独立跨学科研究生涯。青少年吸烟行为的风险， 包括较早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。几条融合的工作线表明 存在多动症症状时吸烟率高可能与常见的遗传因素有关 增加 ND 和 ADHD 风险的漏洞。此外，吸烟的风险也会增加 人群可能与尼古丁和尼古丁戒断对 ADHD 相关缺陷的影响有关 执行功能（EF）和延迟贴现（DD）。该研究计划的重点是阐明 通过检查青少年吸烟的遗传和认知相关性来研究 ND 的神经生物学途径 患有多动症。首先，将对现有遗传信息样本进行二次分析，以解决 文献中的空白涉及 1) 潜在的遗传、环境和受环境影响的基因 吸烟/ND 和 ADHD 之间的重叠以及 2) 与测量到的遗传变异相关 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 合并症。很少有遗传学研究同时检查多动症和吸烟 这项工作将有助于表征表型并选择与最相关的测量基因 这个病因学途径，就是青少年吸烟时存在多动症症状。二、新 将使用实验室药理学方法收集数据以探讨认知和遗传机制 通过评估尼古丁的影响，发现患有多动症的青少年吸烟的潜在风险增加 患有和不患有 ADHD 的青少年吸烟者对 EF 和 DD 的戒断。 EF 和 DD 性能将 经过 24 小时生化验证后，对患有 (n=32) 和不患有 (n=32) ADHD 的青少年吸烟者进行比较 在以下情况下戒烟：1) 安慰剂贴片（尼古丁戒断）和 2) 14 毫克尼古丁 贴片（尼古丁替代品）。还将收集 DNA 以测试遗传的调节作用 EF 和 DD 过程中与尼古丁神经药理学相关的变化。结果将告知关键 高危人群（即患有多动症的青少年）使用尼古丁的脆弱性，并推动 更广泛地了解 ND 的病因因素。这项研究将带来后续资助 应用进一步探讨与吸烟风险相关的遗传和神经药理学机制 ADHD 的存在以及在这个高风险地区开发更有效的 ND 干预措施的临床项目 风险组。为了使 PI 能够追求这一长期研究议程，她将与经验丰富的导师合作 以她目前在多动症神经认知表型方面的专业知识为基础，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）特殊问题 青少年吸烟研究，4) 行为遗传分析方法，以及 5) 综合这些培训 ND 研究计划的长期药物遗传学的经验。综合起来，建议 研究和培训计划的一个关键优先事项是整合遗传和药理学方法，以 增进对 ND 病因和治疗因素的了解，这将为 PI 做好充分准备 该领域的独立临床研究生涯。