Genetic influences on developmental heterogeneity of alcohol use disorder

描述（由申请人提供）：本K01提案的总体目标是探索酒精使用障碍（AUD）发育异质性的遗传影响。澳大利亚影响了相当大比例的美国成年人，与各种精神和医学问题有关，对人类健康构成了重大而昂贵的负担。研究表明，澳元负债是遗传因素和环境因素共同作用的结果，导致问题的表现形式差异很大。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”AUD中达到顶峰。提高对AUD病因的了解有助于预防、干预和治疗，提高在发展早期识别问题的能力，并以有针对性、适当和有效的方式解决这些问题。该建议为候选人描述了一系列培训和研究目标，以努力推进对AUD发展异质性的理解，并阐明遗传影响如何促成这种差异：i)候选人将通过住院和社区精神卫生治疗环境的临床经验建立AUD发展和表现方面的专业知识；通过有组织的阅读以及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酒精使用/滥用的发展以及从青春期到成年早期的相关行为，最终形成一种表型，该表型捕获了个体在不同发展途径中加入AUD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)将对使用纵向建模构建的表型进行全基因组关联研究（GWAS）。候选人将发展一系列复杂的二级分析技能，包括基于基因、基于网络和基于本体的分析，以及更多的基因组风险全球评估，如构建多基因风险评分和探索不同途径的遗传性；iv)

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.