Genetic influences on developmental heterogeneity of alcohol use disorder

描述(由申请人提供)：本K01提案的首要目标是探索遗传对酒精使用障碍(AUD)发育异质性的影响。AUD影响了相当大比例的美国成年人，与各种精神和医疗问题有关，对人类健康构成了重大且代价高昂的负担。研究表明，澳门氏症的风险是遗传因素和环境因素共同作用的结果，这两个因素导致问题的表现形式千差万别。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。通过提高在发育早期发现问题并以有针对性、适当和有效的方式解决问题的能力，对AUD病因的更好理解有助于预防、干预和治疗方面的努力。该提案为候选人勾画了一系列培训和研究目标，以努力促进对AUD发育异质性的理解，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精神卫生治疗环境中的临床经验，以及通过与导师和共同导师的系统阅读和讨论，在AUD的发展和表现方面建立专业知识；Ii)将使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，该表型捕捉个体在不同发育途径中成为AUD成员的可能性(例如，一条与冲动行为有关，另一条与抑郁症状相关，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)。候选人将在一系列复杂的二次分析中培养技能，包括基于基因、基于网络和基于本体的分析，以及对基因组风险的更多全球评估，例如构建多基因风险评分和探索不同途径的遗传性；以及 侯选人将利用以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，其中通过对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/耐受性范例中得到验证。随后，生物信息学和分子遗传学技术在果蝇中的应用将被用来产生进一步探索人类基因组数据的其他候选对象。制度环境非常适合候选人制定酒精研究综合计划的目标，拟议的研究代表着通过结合临床、流行病学、基因组和翻译方法来促进对AUD的理解的重要贡献，与NIAAA的使命一致。 与公共卫生相关：酒精使用障碍影响着20%-30%的美国成年人，并会产生包括精神和医学共病在内的广泛后果，是一个重大的公共卫生问题。该项目旨在阐明遗传因素对从青春期到成年期的酒精滥用和相关行为的影响，并结合临床、流行病学和翻译方法。从这项研究中获得的见解将通过澄清酒精使用问题的发展途径的病因学来为预防、干预和治疗工作提供信息。

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. PUBLIC HEALTH RELEVANCE: Affecting 20-30% of US adults, and with wide-ranging consequences including psychiatric and medical comorbidities, alcohol use disorders represent a significant public health concern. This project aims to elucidate the influence of genetic factor on alcohol misuse and related behaviors from adolescence through adulthood, and integrates clinical, epidemiological, and translational approaches. Insights gained from this research will inform prevention, intervention, and treatment efforts by clarifying the etiology of developmental paths to alcohol use problems.