Genetics, Romantic Relationships, and Alcohol Misuse in Emerging Adulthood

 描述（由申请人提供）：拟议的K 01指导研究科学家发展奖的目的是为候选人提供所需的研究培训经验，以支持她成为一名酒精调查员的职业目标，其目的是了解遗传因素和酒精滥用的发病，持续性和不连续性（即，危险饮酒和酒精使用障碍）。为了扩展她的研究生涯并支持这一职业目标，候选人在该奖项下的培训目标是：（1）建立对成年期酒精滥用的综合理解，将她在酒精结果，浪漫关系和行为遗传学方面的研究兴趣正式联系在一起;（2）在使用和解释高级遗传学方面打下坚实的基础（例如，下一代测序），基因组（例如，功能注释），和统计（例如，结构方程模型）的方法，需要进行一个独立的跨学科的研究计划的基因-环境相互作用的发展酒精滥用。这些目标将通过一系列结构化的指导研究经验，分子遗传学实验室轮换，生物信息学和统计遗传学课程/研讨会，指导阅读导师和合作者谁是各自领域的专家，以及接触危险/有害饮酒的临床干预措施来实现。候选人还将参加其他活动，以进一步支持她的职业发展，包括在负责任的研究行为，赠款写作，并在专业会议上介绍研究的培训。候选人将在Danielle Dick博士的主要指导下在弗吉尼亚联邦大学（VCU）完成此培训（酒精使用障碍的基因-环境相互作用方面的专业知识），由托马斯迪希恩博士提供共同指导（专门研究青少年和成人物质使用途径，重点是人际因素），米哈伊尔·多兹莫罗夫博士（生物信息学和生物统计学方面的专业知识）和Shaunna Clark博士（结构方程建模方面的专业知识）。酒精和行为遗传学是VCU研究的活跃领域，因此候选人拥有无与伦比的支持和资源来促进她的研究事业。这项提案的科学目标是研究酒精依赖遗传倾向如何影响成年期（18-29岁）关系质量和伴侣选择的途径，以及一个人的关系和伴侣的特征如何进一步塑造酒精滥用的轨迹。核心假设是基因-环境相关（rGE）和基因-环境相互作用（G x E）过程有助于这些途径和轨迹。候选人的方法利用生物信息学的新培训，通过创建生物学精炼的多基因评分来表征酒精依赖的总遗传风险。然后，候选人将使用生物学精炼的多基因评分来测试基因-环境相互作用假设，这两项研究是由NIAAA资助的新兴成年人的遗传信息前瞻性纵向研究：Spit for Science（PI：Dick和Kendler）和Project Alliance 1（PAL-1）Relationship Study（PI：Dishion）。Spit for Science是一项每年跟踪（年龄约18-23岁）的四组大学新生（n~ 10，000）样本。PAL-1关系研究是一个样本约400浪漫的二人组（年龄约28-29）。从青春期开始，研究者就开始研究每对夫妻中的一个伴侣，并收集了一对夫妇的评估录像和二元纵向表型数据作为关系研究的一部分。这些研究相辅相成，因为Spit for Science允许候选人研究假设的基因与环境相互作用效应如何在涵盖成年初显的六年期间展开，而PAL-1将提供有关假设效应如何发挥的见解。在成年初显后期的特定二元关系中发挥作用。这项工作的三个目的是：（1）检查酒精依赖遗传倾向是否与一个人的关系质量或一个人的浪漫伴侣的酒精滥用有关（即，rGE），以及这些关联是否由青少年时期的反社会行为和与越轨同龄人的联系介导;（2）检查一个人的关系质量或一个人的浪漫伴侣的酒精滥用是否适度酒精依赖遗传倾向，以预测酒精滥用（即，（3）检查目标1和2中观察到的模式是否因性别而异。这项研究意义重大，因为它满足了对成年期酒精滥用和浪漫关系因素的基因-环境相互作用研究的迫切需要，这是酒精使用障碍发展的最高风险时期。此外，候选人的建议，整合酒精依赖全基因组关联研究结果和功能注释信息，以开发生物精炼的多基因评分是一个创新的出发点，从候选基因的方法通常采用在酒精研究中的基因-环境相互作用的研究。总之，拟议的奖项将为候选人提供新的研究和培训经验，需要启动一个独立的，创新的研究计划，遗传学，浪漫的关系，和酒精滥用，是相关的NIAAA的使命，以确定如何遗传和突出的环境风险和保护因素酒精滥用接口跨发展。

 DESCRIPTION (provided by applicant): The purpose of the proposed K01 Mentored Research Scientist Development Award is to provide the candidate with research training experiences needed to support her career goal of becoming an alcohol investigator who aims to understand the interplay between genetic factors and close relationship factors in the onset, persistence, and discontinuity of alcohol misuse (i.e., risky drinking and alcohol use disorder). To expand her research career and support this career goal, the candidate's training goals under this award are to: (1) establish an integrated understanding of alcohol misuse in emerging adulthood that formally ties together her research interests in alcohol outcomes, romantic relationships, and behavior genetics; and (2) develop a solid foundation in the use and interpretation of advanced genetic (e.g., next generation sequencing), genomic (e.g., functional annotation), and statistical (e.g., structural equation modeling) methods needed to carry out an independent interdisciplinary program of research on gene-environment interplay in the development of alcohol misuse. These goals will be achieved through a structured series of mentored research experiences, a molecular genetics laboratory rotation, coursework/workshops in bioinformatics and statistical genetics, directed readings with mentors and collaborators who are experts in their respective fields, and exposure to clinical interventions for hazardous/harmful drinking. The candidate will also participate in additional activities to further support her career development including training in the responsible conduct of research, grant writing, and presenting research at professional conferences. The candidate will complete this training at Virginia Commonwealth University (VCU) under the primary mentorship of Dr. Danielle Dick (expertise in gene-environment interplay for alcohol use disorder), with co-mentorship provided by Dr. Thomas Dishion (expertise in pathways toward adolescent and adult substance use, with an emphasis on interpersonal factors), Dr. Mikhail Dozmorov (expertise in bioinformatics and biostatistics), and Dr. Shaunna Clark (expertise in structural equation modeling). Alcohol and behavior genetics are active areas of research at VCU, and thus the candidate has unparalleled support and resources to further her research career. The scientific objective of this proposal is to examine how alcohol dependence genetic predispositions influence pathways to emerging adulthood (ages 18-29) relationship quality and partner selection, and how characteristics of one's relationship and partner further shape trajectories of alcohol misuse. The central hypothesis is that gene-environment correlation (rGE) and gene-environment interaction (G x E) processes contribute to these pathways and trajectories. The candidate's approach leverages novel training in bioinformatics to characterize aggregate genetic risk for alcohol dependence by creating biologically refined polygenic scores. The candidate will then use biologically refined polygenic scores to test gene-environment interplay hypotheses in two NIAAA-funded genetically informative prospective longitudinal studies of emerging adults: Spit for Science (PIs: Dick and Kendler) and the Project Alliance 1 (PAL-1) Relationship Study (PI: Dishion). Spit for Science is a sample of four cohorts of college freshmen (n~10,000) who are followed annually (ages ~18-23). The PAL-1 Relationship Study is a sample of ~400 romantic dyads (ages ~28-29). One partner in each dyad has been studied since adolescence, and a videotaped couple's assessment and dyadic longitudinal phenotypic data are collected as part of the relationship study. These studies complement one another in that Spit for Science allows the candidate to examine how the hypothesized gene-environment interplay effects unfold across a six-year period covering the beginning of emerging adulthood, and PAL-1 will provide insights into how the hypothesized effects play out in a specific dyadic relationship in the latter part of emerging adulthood. The three aims of this work are to: (1) Examine whether alcohol dependence genetic predispositions are associated with the quality of one's relationship or the alcohol misuse of one's romantic partner (i.e., rGE), and whether these associations are mediated by antisocial behavior and affiliations with deviant peers in adolescence; (2) Examine whether the quality of one's relationship or the alcohol misuse of one's romantic partner moderate alcohol dependence genetic predispositions to predict alcohol misuse (i.e., G x E); (3) Examine whether the patterns observed in Aims 1 and 2 differ by sex. This research is significant because it fills a critical need for studies of gene-environment interplay for alcohol misuse and romantic relationship factors in emerging adulthood, which is the period of highest risk for the development of alcohol use disorder. Furthermore, the candidate's proposal to integrate alcohol dependence genome-wide association study results and functional annotation information to develop biologically refined polygenic scores is an innovative departure from the candidate gene approach typically adopted in studies of gene-environment interplay in alcohol research. In summary, the proposed award will provide the candidate with new research and training experiences needed to launch an independent, innovative research program on genetics, romantic relationships, and alcohol misuse that is relevant to NIAAA's mission to identify how genetic and salient environmental risk and protective factors for alcohol misuse interface across development.