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.

项目摘要 这项K23奖推进了候选人将药物遗传学和精神病学相结合的长期目标 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 缺乏性多动障碍(ADHD)。拟议的培训将使PI能够发展所需的技能 在这一领域有独立的跨学科研究生涯。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，与临床上的 ADHD的诊断和非临床水平的ADHD症状。几个汇聚在一起的工作表明 出现ADHD症状时的高吸烟率可能与共同的基因有关 增加ND和ADHD风险的漏洞。此外，在这种情况下吸烟的风险增加 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)和延迟折扣(DD)。研究计划的重点是阐明一种 青少年吸烟与遗传和认知相关的神经生物学途径 患有多动症。首先，将对现有的遗传信息样本进行二次分析，以解决 文献中与1)环境影响潜在的遗传、环境和基因有关的空白 吸烟/新城疫和ADHD之间的重叠以及2)与测量的与以下方面相关的遗传变异的关联 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测ADHD和吸烟。 这项工作将有助于表征表型和选择与基因最相关的测量基因 这一致病途径，即青少年吸烟时出现的ADHD症状。第二，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，揭示青少年ADHD患者吸烟风险的潜在增加 伴和不伴ADHD的青少年吸烟者的EF和DD戒断情况。EF和DD的性能将是 对患有和不患有ADHD的青少年吸烟者进行24小时生化验证后的比较 在下列情况下戒烟：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，以测试基因的调节作用 EF和DD突起的变异与尼古丁神经药理学有关。结果将通知一名危重患者 在高危人群，即患有ADHD的青少年中，尼古丁使用的脆弱性，并促进 对ND的病因有更广泛的认识。这项研究将导致后续的拨款 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，以开发更有效的干预措施，在这个高度- 风险组。为了使私人助理能够从事这项长期的研究议程，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)行为药理学的实验室方法，3) 青少年吸烟研究，4)行为遗传分析方法，5)综合这些训练 经验纳入新城疫长期药物遗传学研究计划。总而言之，拟议的 研究和培训计划涉及整合遗传和药理学方法的关键优先事项 提高对新城疫病因和治疗因素的认识，为预防新城疫做好充分准备 在该领域的独立临床研究生涯。