Genetics, Romantic Relationships, and Alcohol Misuse in Emerging Adulthood

 描述(申请人提供)：K01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，旨在了解遗传因素和密切关系因素在酒精滥用(即高风险饮酒和酒精使用障碍)的发生、持续和中断中的相互作用。为了扩大她的研究生涯并支持这个职业目标，候选人在这个奖项下的培训目标是：(1)建立对成年初期酒精滥用的综合理解，将她在酒精结果、恋爱关系和行为遗传学方面的研究兴趣正式联系在一起；以及(2)在使用和解释先进的遗传学(例如下一代测序)、基因组(例如功能注释)和统计学(例如结构方程建模)方法方面奠定坚实的基础，该方法需要进行独立的跨学科计划，研究酒精滥用发生中基因与环境的相互作用。这些目标将通过一系列有指导的研究经验、分子遗传学实验室轮换、生物信息学和统计遗传学的课程作业/研讨会、与各自领域的专家导师和合作者的定向阅读以及接触危险/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，包括负责任地进行研究、撰写补助金和在专业会议上发表研究报告的培训。候选人将在弗吉尼亚联邦大学(VCU)完成这项培训，主要导师是Danielle Dick博士(酒精使用障碍的基因-环境相互作用方面的专业知识)，共同导师是Thomas Dishion博士(青少年和成人物质使用途径方面的专业知识，重点是人际因素)、Mikhail Dozmorov博士(生物信息学和生物统计学专业知识)和Shaunna Clark博士(结构方程建模专业知识)。酒精和行为遗传学是弗吉尼亚州立大学活跃的研究领域，因此候选人拥有无与伦比的支持和资源来推进她的研究事业。这项建议的科学目标是研究酒精依赖的遗传倾向如何影响成年后(18-29岁)的关系质量和伴侣选择，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。中心假设是基因-环境相关(RGE)和基因-环境相互作用(G×E)过程促成了这些路径和轨迹。候选人的方法利用生物信息学中的新培训，通过创建生物精炼的多基因得分来表征酒精依赖的总遗传风险。然后，候选人将使用生物精炼的多基因分数来测试两项由NIAAA资助的针对新兴成年人的遗传信息前瞻性纵向研究中的基因-环境相互作用假说：为科学而吐口水(PI：Dick和Kendler)和项目联盟1(PAL-1)关系研究(PI：Dishion)。《为科学吐口水》是四个大学新生(n~10,000)的样本，他们每年都会被跟踪调查(年龄在18-23岁之间)。PAL-1关系研究是对大约400名浪漫二人组(年龄在28-29岁之间)的研究。从青春期开始，研究人员对每对夫妇中的一个伴侣进行了研究，并收集了一对夫妇的评估录像和纵向表型数据，作为关系研究的一部分。这些研究是相辅相成的，因为科学唾液允许考生检验假设的基因-环境相互作用效应是如何在六年的时间里展开的，而PAL-1将提供关于假设的效应如何在新兴成年后期的特定二元关系中发挥作用的见解。这项工作的三个目的是：(1)考察酒精依赖遗传倾向是否与一个人的关系质量或其浪漫伴侣的酒精滥用(即RGE)有关，以及这些联系是否由反社会行为和青春期与偏差同龄人的联系所调节；(2)检查一个人的关系质量或其浪漫伴侣的酒精滥用是否适度预测酒精滥用的遗传倾向(即，G×E)；(3)检查目标1和2中观察到的模式是否因性别而不同。这项研究具有重要意义，因为它填补了对酒精滥用的基因-环境相互作用以及成年初期浪漫关系因素研究的迫切需要，成年初期是酒精使用障碍发展的最高风险时期。此外，候选人提出的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细化多基因评分的建议，是对酒精研究中基因-环境相互作用研究中通常采用的候选基因方法的创新。总之，拟议的奖项将为候选人提供新的研究和培训经验，以启动一项关于遗传学、恋爱关系和酒精滥用的独立、创新的研究计划，该计划与NIAAA的使命相关，即确定酒精滥用的遗传和显著环境风险以及保护因素如何在发育过程中相互作用。

 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.