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

了解可改变的生活方式和心理社会因素在缓解退伍军人饮酒问题遗传风险中的作用

• 批准号: 10657615
• 负责人: Peter Na
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657615
• 关键词: Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcohol dependence; Alcohols; Animals; Area; Biological; Biological Process; Candidate Disease Gene; Childhood; Chronic; Clinical; Clinical Research; Collaborations; Data; Data Set; Diagnostic; Disease; Drug usage; Educational workshop; Enzymes; Epidemiology; Etiology; Frequencies; Genes; Genetic; Genetic Research; Genetic Risk; Grant; Health; Healthcare; Institution; Intervention; K-Series Research Career Programs; Knowledge; Life; Life Style; Link; Literature; Logistic Regressions; Measures; Mentors; Methods; Molecular; Pharmaceutical Preparations; Phenotype; Physical Exercise; Pilot Projects; Populations at Risk; Positioning Attribute; Predisposition; Prevention; Process; Prospective cohort; Psychiatric epidemiology; Psychiatrist; Psychosocial Assessment and Care; Psychosocial Factor; Public Health; Regression Analysis; Research; Research Methodology; Research Personnel; Research Priority; Research Project Grants; Research Support; Research Training; Risk Assessment; Risk Factors; Role; Sampling; Social support; Structure; Substance Use Disorder; Testing; Training; Trauma; Universities; Veterans; Veterans Health Administration; Work; alcohol use disorder; biobank; biopsychosocial; candidate identification; care burden; career; clinical practice; cohort; experience; follow-up; functional genomics; gene environment interaction; genetic variant; genome wide association study; genome-wide; large datasets; lifestyle factors; military veteran; modifiable lifestyle factors; nicotine use; optimism; polygenic risk score; precision medicine; prevent; programs; protective factors; psychiatric genomics; psychogenetics; psychosocial; resilience; skills; training project; trait; variant detection

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.

当前的职业发展奖级1（CDA-1）提案将扩大彼得·纳（Peter Na）博士 研究范围通过全面培训来纳入精神病遗传学技能 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学 流行病学。他的导师是精神病学和心理社会领域的领先专家 流行病学 - 博士。 Joel Gelernter，Robert Pietrzak和Renato Polimanti，博士合作 Hang Zhou，计算生物学家。 NA博士还将通过高级接受其他培训 耶鲁大学和其他机构提供的讲习班，半岛和课程。提议 研究项目将调查环境（例如创伤负荷），社会心理（例如，人生目的）， 和生活方式（例如体育锻炼）（EPL）对酒精易感性的因素 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） 世界上最大的当代基因组协会研究（GWAS）。此外， 拟议的研究将促进该领域对AUD的生物心理社会病因的理解 使用尖端的遗传研究方法（例如基因富集）的饮酒 和药物替代分析。尽管在理解遗传学方面取得了进步 AUD和社会心理风险和这种疾病的保护因素，生物学之间的相互作用 预测AUD的EPL因素仍然知之甚少。为了解决这个差距，提议 研究旨在确定使用多个的EPL因子对退伍军人的AUD中等多基因责任 大型数据集，包括百万退伍军人计划（MVP），国家健康和韧性 退伍军人研究（NHRVS）和耶鲁·佩恩（Yale-Penn）研究。这一研究直接解决了顶部 退伍军人卫生管理局（VHA）和此RFA的优先研究领域（即 疾病，精密医学，老兵伯恩（Burnen）的疾病）。调节 拟议的研究中确定的EPL变量将阐明临床干预措施的靶标，以防止 并在退伍军人中对待AUD，并最终帮助指导VA临床实践。 PR将使用 来自MVP队列的AUD的GWA（n = 267,391），来自精神病的酒精依赖性 基因组学联盟（n = 46,568），源自酒精的数量频率特征 英国生物银行（n = 121,604）和饮酒的疾病识别测试 （每周饮料）来自GSCAN（GWAS和测序联盟，酒精和尼古丁的使用财团； n = 537,352）。潜在的调节EPL因子将根据先前的文献选择。这 PR，选定的EPL因子及其在预测AUD和酒精方面的相互作用之间的关联 将使用二项式和多项式逻辑回归分析来检查消费。 PR 将进行富集分析以检查受相互作用影响的生物学过程。 此外，将进行药物重新定位分析以检查生物学机制和 确定可能在动物和试点研究中进一步测试的AUD的候选药物。之上 在第二年底，成功完成了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，这些数据将用于购买更大的赠款和 继续研究支持，例如CDA-2。这种培训将对他的进一步发展 研究知识和技能在他从事独立临床研究职业时作为VA 精神科医生。