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: 8507197
• 负责人: L. Cinnamon Bidwell
• 金额: $ 17.4万
• 依托单位: BROWN UNIVERSITY
• 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/8507197
• 关键词: Abstinence; Accounting; Address; Adolescent; Age; Applications Grants; Architecture; Area; Attention deficit hyperactivity disorder; Behavioral Genetics; 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; Interdisciplinary Study; Investigation; Laboratories; Lead; Literature; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolism; Methodology; Methods; Neurobiology; Neurocognitive; Neuropharmacology; Nicotine; Nicotine Dependence; 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

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.

描述（由申请人提供）：该K23奖在吸烟/尼古丁依赖性（ND）研究中将候选人的长期目标促进了将药物遗传学和精神遗传方法整合在一起的长期目标及其与注意力缺陷多功能障碍（ADHD）的共同存在。拟议的培训将使PI能够发展该领域独立跨学科研究所需的技能。青少年吸烟行为的风险，包括较早的起始年龄和定期吸烟的可能性，与多动症的临床诊断和非临床水平的ADHD症状有关。几种融合的工作线表明，存在多动症症状的高吸烟率可能与常见的遗传脆弱性有关，这些遗传脆弱性增加了ND和ADHD的风险。此外，该人群中吸烟的风险增加可能与尼古丁和尼古丁戒酒对执行功能（EF）（EF）和延迟折现（DD）的缺陷的影响有关。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，以解决与1）与1）通过环境对吸烟/ND和ADHD的重叠的潜在遗传，环境和基因相关的差距代谢基因）和ND/ADHD合并症。这项工作将有助于表征与青少年吸烟的遗传研究最相关的表型，尤其是在ADHD症状存在的情况下，并选择了该病因学途径的测量基因。其次，将使用实验室药理学方法收集新数据，以探测ADHD青少年吸烟风险增加的认知和遗传机制，通过评估有或没有ADHD的青少年吸烟者的EF和DD的影响，从而增加了ADHD的吸烟风险。在以下条件下24小时生物化学验证的吸烟戒烟后，将比较（n = 32）和没有（n = 32）ADHD的青少年吸烟者的EF和DD性能：1）安慰剂贴剂（尼古丁戒烟）和2）14 mg Nicotine Patch（尼古丁替代品）。还将收集DNA，以测试与尼古丁神经 - 药理学在EF和DD过程中有关的遗传变异的调节作用。结果将为高风险人群（即患有多动症的青少年）的尼古丁使用的关键脆弱性，并在更广泛的情况下提高对病因学因素的理解。这项研究将导致随后的授予申请，以进一步探测与ADHD存在的吸烟风险以及临床项目相关的遗传和神经药理机制，以在此高风险群体中为ND开发更有效的干预措施。为了使PI能够追求这一长期研究议程，她将与经验丰富的指导者合作，基于她在ADHD神经认知表型的当前专业知识，并在五个培训领域：（1）尼古丁心理药理学，2）行为药理学领域的实验室方法，3）3）青少年吸烟的现象学，4）先进的行为原理原理和5）。综上所述，拟议的研究和培训计划介绍了整合遗传学和药理方法的关键优先事项，以提高对ND中病因和治疗因素的理解，这将为该领域的独立临床研究职业做好准备。