Genetic influences on developmental heterogeneity of alcohol use disorder

遗传对酒精使用障碍发育异质性的影响

• 批准号: 8517523
• 负责人: ALEXIS C EDWARDS
• 金额: $ 13.44万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517523
• 关键词: Accounting; Acute; Address; Adolescence; Adult; Affect; Age of Onset; Alcohol abuse; Alcohol consumption; Alcohols; Attention deficit hyperactivity disorder; Behavior; Behavioral; Bioinformatics; Biological; Biological Factors; Biological Models; Candidate Disease Gene; Childhood; Clinical; Communities; Comorbidity; Conduct Disorder; Data; Development; Diagnostic and Statistical Manual; Drosophila genus; Drosophila melanogaster; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Etiology; Exposure to; Failure; Foundations; Future; Genes; Genetic; Genetic Techniques; Genomics; Goals; Growth; Health; Heritability; Heterogeneity; Human; Immersion Investigative Technique; Impulsive Behavior; Individual; Inpatients; Investigation; Literature; Measures; Mediator of activation protein; Medical; Mental Health; Mentors; Methods; Mission; Modeling; Molecular Genetics; National Institute on Alcohol Abuse and Alcoholism; Nature; Network-based; Ontology; Outcome; Pathway interactions; Pattern; Phenotype; Population; Prevalence; Prevention; Preventive Intervention; Process; Public Health; Quantitative Genetics; Reading; Research; Research Personnel; Research Training; Risk; Risk Factors; Secondary to; Series; Structure; Syndrome; System; Training; Training Activity; Translating; Twin Multiple Birth; Variant; alcohol misuse; alcohol related problem; alcohol research; alcohol response; alcohol sensitivity; alcohol use disorder; base; career development; depressive symptoms; emerging adult; experience; gene environment interaction; genome wide association study; improved; insight; interest; problem drinker; programs; psychologic; research study; risk variant; skills; trait; translational approach

DESCRIPTION (provided by applicant): The overarching goal of this K01 proposal is to explore genetic influences on the developmental heterogeneity of alcohol use disorder (AUD). AUD affects a substantial proportion of US adults, is associated with a variety of psychiatric and medical problems, and represents a significant and costly burden to human health. Research indicates that AUD liability is a function of both genetic and environmental factors, which contribute to wide variation in the manifestation of problems. Epidemiological studies strongly suggest that the development of alcohol problems and related behaviors begins in adolescence, and culminates in the various "types" of AUD described in the alcohol research literature. An improved understanding of the etiology of AUD can contribute to efforts in prevention, intervention, and treatment by advancing the ability to identify problems early in development and address them in a targeted, appropriate, and effective manner. This proposal delineates a series of training and research goals for the candidate in an effort to advance the understanding of the developmental heterogeneity of AUD and clarify how genetic influences contribute to this variation: i) the candidate will establish expertise in the development and manifestation of AUD through clinical experience in both inpatient and community mental health treatment settings; and through structured readings and discussions with the mentor and co-mentor; ii) a variety of longitudinal modeling methods will be employed to explore the development of alcohol use/misuse alongside associated behaviors from adolescence to early adulthood, culminating in a phenotype that captures an individual's likelihood of membership in different developmental pathways to AUD (e.g., one associated with impulsive behavior, another with depressive symptoms, etc.); iii) genome-wide association studies (GWAS) will be conducted on the phenotypes constructed using longitudinal modeling. The candidate will develop skills in a host of sophisticated secondary analyses including gene-based, network-based, and ontology-based analyses, as well as more global assessments of genomic risk such as the construction of polygenic risk scores and exploration of the heritability of different pathways to AUD; and iv) the candidate will capitalize on previously established expertise in Drosophila genomics to establish a translational program of research, wherein promising candidates identified through the secondary analyses of GWAS data will be validated in a Drosophila alcohol sensitivity/tolerance paradigm. Subsequently, the application of bioinformatic and molecular genetic techniques in Drosophila will be used to generate additional candidates for further exploration in human genomic data. The institutional environment is ideal for the candidate's goal of developing a comprehensive program in alcohol research, and the proposed research represents an important contribution toward advancing the understanding of AUD through a combination of clinical, epidemiological, genomic, and translational methods, consistent with the mission of the NIAAA.

描述（由申请人提供）：该 K01 提案的总体目标是探索遗传对酒精使用障碍 (AUD) 发育异质性的影响。 AUD 影响着相当大比例的美国成年人，与各种精神和医疗问题有关，并且对人类健康构成了重大且昂贵的负担。研究表明，澳元责任是遗传因素和环境因素共同作用的结果，导致问题表现形式存在很大差异。流行病学研究强烈表明，酒精问题和相关行为的发展始于青春期，并在酒精研究文献中描述的各种“类型”的 AUD 中达到顶峰。加深对 AUD 病因的了解，有助于提高在发展早期发现问题并有针对性、适当和有效地解决问题的能力，从而有助于预防、干预和治疗。 该提案为候选人描绘了一系列培训和研究目标，以加深对 AUD 发展异质性的理解，并阐明遗传影响如何导致这种变异： i) 候选人将通过住院和社区心理健康治疗环境中的临床经验，建立 AUD 发展和表现方面的专业知识；以及通过结构化阅读和与导师和共同导师的讨论； ii) 将采用各种纵向建模方法来探索从青春期到成年早期酒精使用/滥用以及相关行为的发展，最终形成一种表型，该表型捕获个体参与不同 AUD 发展途径的可能性（例如，一种与冲动行为相关，另一种与抑郁症状相关，等等）； iii) 将针对使用纵向模型构建的表型进行全基因组关联研究（GWAS）。候选人将培养一系列复杂的二次分析技能，包括基于基因、基于网络和基于本体的分析，以及对基因组风险进行更全面的评估，例如构建多基因风险评分和探索不同 AUD 途径的遗传性；和 iv) 候选人将利用先前在果蝇基因组学方面建立的专业知识来建立一个转化研究计划，其中通过 GWAS 数据的二次分析确定的有前途的候选人将在果蝇酒精敏感性/耐受性范式中得到验证。随后，生物信息学和分子遗传学技术在果蝇中的应用将用于生成更多候选者，以进一步探索人类基因组数据。该机构环境非常适合候选人开发酒精研究综合项目的目标，并且拟议的研究通过结合临床、流行病学、基因组和转化方法，为促进对 AUD 的理解做出了重要贡献，这与 NIAAA 的使命一致。