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.

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遗传学技能 精神病基因组学、统计遗传学、功能基因组学和高级精神病学 他的导师是遗传遗传学和心理社会领域的顶尖专家。 流行病学 - Joel Gelernter 博士、Robert Pietrzak 博士和 Renato Polimanti 博士与 Dr. 合作 计算生物学家周航也将接受高级培训。 耶鲁大学和其他机构提供的讲习班、研讨会和课程。 研究项目将调查环境（例如创伤负荷）、社会心理（例如生活目的）、 调节多基因酒精易感性的生活方式（例如体育锻炼）（EPL）因素 使用最先进的多基因风险评分（PRS）计算退伍军人使用障碍（AUD） 世界上最大的针对这种疾病的当代全基因组关联研究（GWAS）。 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 使用尖端基因研究方法（例如基因富集）控制饮酒 和药物重新定位分析虽然在遗传学的理解方面取得了进展。 AUD 与这种疾病的心理社会风险和保护因素、生物之间的相互作用 和 EPL 预测 AUD 的因素仍然知之甚少，为了解决这一差距，提出了建议。 研究旨在确定 EPL 因素，使用多种方法来调节退伍军人 AUD 的多基因责任 大数据集，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直接解决了这一问题。 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、退伍军人医疗负担较高的疾病）。 拟议研究中确定的 EPL 变量将阐明临床干预措施的目标，以预防 治疗退伍军人的 AUD，并最终帮助指导 VA 的临床实践。 来自 MVP 队列 (N=267,391) 的 AUD 的 GWAS，来自精神病学的酒精依赖 基因组学联盟 (N=46,568)，来自酒精使用的数量频率特征 英国生物银行的疾病识别测试 (N=121,604) 和饮酒情况 （每周饮酒量）来自 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 EPL 调节因素。 PRS、选定的 EPL 因素之间的关联及其在预测 AUD 和酒精方面的相互作用 将使用二项式和多项逻辑回归分析来检查消费量。 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学机制和 确定可在动物和试点研究中进一步测试的 AUD 候选药物。 在第二年年底成功完成拟议的培训和研究项目后，那博士将 获得足够的专业知识和初步数据，用于寻求更大的赠款和 持续的研究支持，例如 CDA-2，此类培训将有助于他的进一步发展。 作为一名退伍军人，他追求独立的临床研究职业，同时研究知识和技能 精神。