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: 8902748
• 负责人: ALEXIS C EDWARDS
• 金额: $ 14.45万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902748
• 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 of Mental Disorders; 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对酒精使用障碍（AUD）发育异质性的遗传影响。 AUD会影响美国成年人中很大一部分，与各种精神病和医学问题有关，这代表了人类健康的巨大且昂贵的负担。研究表明，AUD责任是遗传和环境因素的函数，这导致问题表现的广泛差异。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中达到顶点。对AUD病因的了解可以提高对预防，干预和治疗的努力，从而提高开发早期识别问题并以有针对性，适当和有效的方式解决问题，从而有助于预防，干预和治疗。 该提案描述了候选人的一系列培训和研究目标，以促进对AUD的发展异质性的理解，并阐明遗传影响如何对这种变化有何贡献：i）i）候选人将通过在患者和社区心理健康治疗环境中通过临床经验来建立AUD的发展和表现方面的专业知识；并通过与导师和同事的结构化阅读和讨论； ii）将采用各种纵向建模方法来探索酒精使用/滥用的发展以及从青春期到成年初期的相关行为，最终以一种表型为导致捕获个人成员在不同发展途径中成员的可能性（例如，一种与冲动性行为相关的，另一种与抑郁症状相关的）； III）全基因组关联研究（GWAS）将对使用纵向建模构建的表型进行。候选人将在许多复杂的二级分析中发展技能，包括基于基因的，基于网络和基于本体的分析，以及对基因组风险的全球评估，例如建立多基因风险评分以及探索AUD的不同途径的遗传力；和iv） 候选人将利用果蝇基因组学先前建立的专业知识，以建立一项转化计划，其中通过二次分析GWAS数据确定的有希望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，将使用生物信息学和分子遗传技术在果蝇中的应用来生成其他候选者，以在人类基因组数据中进一步探索。制度环境是候选人在酒精研究中制定全面计划的目标的理想选择，而拟议的研究代表了通过临床，流行病学，基因组和翻译方法结合使用与NIAAA的使命相结合的重要贡献。