Understanding the role of modifiable lifestyle and psychosocial factors in moderating genetic risk for alcohol use problems in veterans

目前的职业发展奖1级（CDA-1）提案将扩大彼得纳博士的 研究范围，通过全面的培训， 精神病基因组学，统计遗传学，功能基因组学和先进的精神病 流行病学他的导师是精神遗传学和社会心理学领域的顶尖专家 流行病学-博士乔尔Gelernter，罗伯特Pietrzak，和雷纳托Polimanti，与博士合作。 周航，计算生物学家。Na博士还将通过高级培训进行额外的培训。 耶鲁大学和其他机构提供的讲习班、研讨会和课程。拟议 研究项目将调查环境（例如，创伤负荷），心理社会（例如，生活的目的）， 和生活方式（例如，体育锻炼）（EPL）因素，调节多基因酒精易感性 使用最先进的多基因风险评分（PRS）计算退伍军人的使用障碍（AUD）， 世界上最大的当代全基因组关联研究（GWAS）。此夕h 拟议的研究将促进该领域对AUD的生物心理社会病因学的理解， 使用基因富集等尖端基因研究方法来控制酒精消费 和药物重新定位分析。虽然对遗传学的理解有了进展， AUD与心理社会危险因素和保护因素之间的相互作用， 和EPL因素预测澳元仍然知之甚少。为了弥补这一差距，建议 一项研究的目的是确定EPL的因素，温和的多基因责任的AUD在退伍军人中使用多个 大型数据集，包括百万退伍军人计划（MVP），国家健康和恢复力， 退伍军人研究（NHRVS）和耶鲁-宾夕法尼亚研究。这条研究路线直接针对高层 退伍军人健康管理局（VHA）和本RFA的优先研究领域（即，物质使用 疾病，精准医疗，退伍军人医疗负担高的疾病）。的调节 在拟议的研究中确定的EPL变量将阐明临床干预的目标，以防止 治疗退伍军人的AUD，并最终帮助指导VA临床实践。PRS将使用 MVP队列（N= 267，391）的AUD GWAS，精神病学队列（N= 267，391）的酒精依赖GWAS， Genomics Consortium（N= 46，568），来自酒精使用的数量-频率特征 来自英国生物库的疾病识别测试（N= 121，604）和饮酒 （饮料/周）从GSCAN（GWAS和酒精和尼古丁使用测序联盟; N= 537，352）。将根据以前的文献选择潜在的调节EPL因素。的 PRS、选定EPL因子及其相互作用在预测AUD和酒精中的相关性 将使用二项和多项逻辑回归分析来检查消耗量。PRS 将进行富集分析，以检查受相互作用影响的生物过程。 此外，将进行药物重新定位分析以检查生物机制， 确定可能在动物和初步研究中进一步测试的AUD候选药物。后 在第二年年底前成功完成拟议的培训和研究项目，Na博士将 获得足够的专业知识和初步数据，用于寻求更大的赠款， 持续的研究支持，如CDA-2。这种培训将有助于促进他的 研究知识和技能，因为他追求一个独立的临床研究生涯作为一个VA 心理医生

The current Career Development Award-Level 1 (CDA-1) proposal will expand Dr. Peter Na’s research scope to incorporate psychiatric genetics skills through comprehensive training in psychiatric genomics, statistical genetics, functional genomics and advanced psychiatric epidemiology. His mentors are leading experts in the field of psychiatric genetics and psychosocial epidemiology - Drs. Joel Gelernter, Robert Pietrzak, and Renato Polimanti, with collaboration from Dr. Hang Zhou, a computational biologist. Dr. Na will also pursue additional training through advanced workshops, seminars and courses offered by Yale University and other institutions. The proposed research project will investigate environmental (e.g., trauma load), psychosocial (e.g., purpose in life), and lifestyle (e.g., physical exercise) (EPL) factors that moderate polygenic susceptibility for alcohol use disorder (AUD) in Veterans using state-of-the art polygenic risk scores (PRS) computed from the world’s largest contemporary genome-wide association studies (GWAS) of this disorder. Further, the proposed study will advance the field’s understanding of the biopsychosocial etiology of AUD and alcohol consumption using cutting-edge genetic research methodologies such as gene enrichment and drug-repositioning analyses. While there have been advances in the understanding of genetics of AUD and psychosocial risk and protective factors for this disorder, the interaction between biological and EPL factors in predicting AUD remain poorly understood. To address this gap, the proposed study aims to identify EPL factors that moderate polygenic liability for AUD in Veterans using multiple large data sets, including the Million Veteran Program (MVP), the National Health and Resilience in Veterans Study (NHRVS) and the Yale-Penn Study. This line of research directly addresses the top priority research areas of the Veterans Health Administration (VHA) and this RFA (i.e., substance use disorders, precision medicine, diseases with a high healthcare burden in Veterans). The moderating EPL variables identified in the proposed study will elucidate targets for clinical interventions to prevent and treat AUD in Veterans and ultimately help guide VA clinical practices. PRS will be derived using the GWAS of AUD from the MVP cohort (N=267,391), of alcohol dependence from the Psychiatric Genomics Consortium (N=46,568), of the quantity-frequency trait derived from the Alcohol Use Disorders Identification Test from the UK Biobank (N=121,604), and of alcohol consumption (drinks/week) from GSCAN (GWAS & Sequencing Consortium of Alcohol and Nicotine use; N=537,352). Potential moderating EPL factors will be selected based on previous literature. The associations between PRS, selected EPL factors, and their interaction in predicting AUD and alcohol consumption will be examined using binomial and multinomial logistic regression analyses. PRS enrichment analysis will be conducted to examine the biological processes affected by the interaction. Further, drug repositioning analysis will be performed to examine the biological mechanisms and identify candidate medications for AUD that may be further tested in animal and pilot studies. Upon successful completion of the proposed training and research project by the end of Year 2, Dr. Na will acquire sufficient expertise and preliminary data that will be used to pursue larger grants and continued research support, such as the CDA-2. Such training will be instrumental to furthering his research knowledge and skills as he pursues an independent clinical research career as a VA psychiatrist.