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Peter Na博士的 研究范围通过综合培训纳入精神病学遗传学技能 精神病学基因组学、统计遗传学、功能基因组学和高级精神病学 流行病学。他的导师是精神病学遗传学和心理学领域的顶尖专家。 流行病学--Joel Gelernter博士、Robert Pietrzak博士和Renato Polimanti博士 计算生物学家周航说。纳博士还将通过高级课程继续接受额外的培训 由耶鲁大学和其他机构提供的研讨会、研讨会和课程。建议数 研究项目将调查环境(例如，创伤负荷)、心理社会(例如，生活目标)、 和生活方式(例如，体育锻炼)(EPL)因素对酒精的多基因易感性中等 在退伍军人中使用最先进的多基因风险评分(PR)在退伍军人中使用障碍(AUD) 世界上最大的当代全基因组关联研究(GWAS)这种疾病。此外， 拟议的研究将促进该领域对AUD和AUD的生物心理社会病因学的理解 使用基因浓缩等尖端基因研究方法的饮酒 以及药物重新定位分析。虽然在对遗传学的理解方面取得了进展 AUD与心理社会风险和保护因素之间的相互作用 而EPL因素对AUD的预测仍然知之甚少。为解决这一差距，拟议的 这项研究旨在确定在退伍军人中使用多个多基因来缓解AUD的多基因易感性的EPL因素 大型数据集，包括百万退伍军人计划(MVP)、国家健康和复原力 退伍军人研究(NHRVS)和耶鲁-宾夕法尼亚大学研究。这一系列研究直接针对的是顶层 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、精准医学、退伍军人医疗负担高的疾病)。调和 拟议研究中确定的EPL变量将阐明临床干预的目标，以防止 并治疗退伍军人的AUD，最终帮助指导退伍军人管理局的临床实践。将使用以下方法派生PR 来自MVP队列(N=267,391)的AUD的GWA值，来自精神病患者的酒精依赖 基因组学联盟(N=46,568)，因饮酒而产生的数量-频率性状 来自英国生物库的障碍识别测试(N=121,604)，以及酒精消费 (每周饮酒量)来自GSCAN(Gwas&酒精和尼古丁使用排序联盟； N=537,352)。潜在的调节EPL的因素将根据以前的文献进行选择。这个 在预测AUD和酒精方面，精神分裂症和部分EPL因素之间的关联及其相互作用 消费将使用二项和多项Logistic回归分析进行检验。复苏术 将进行浓缩分析，以检查相互作用影响的生物过程。 此外，还将进行药物重新定位分析，以检查生物机制和 确定治疗AUD的候选药物，这些药物可能会在动物和试点研究中进一步测试。vt.在.的基础上 在第二年年底前成功完成拟议的培训和研究项目，纳博士将 获得足够的专业知识和初步数据，用于争取更大的赠款和 持续的研究支持，如CDA-2。这样的培训将有助于进一步发展他的 研究知识和技能，因为他追求独立的临床研究生涯作为退伍军人管理局 精神病学家。

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.