Relations between alcohol use, aggression, executive function, and ADHD: a genetic analysis

项目摘要/摘要 长期目标：本应用程序的首要目标是(1)利用高级多元变量 全基因组关联研究(GWAS)方法，以改进目前的模型之间的关系 攻击性、酒精使用、执行功能和注意力缺陷多动障碍(ADHD)，以及(2)适用 改进的遗传易感性建模技术用于预测人群间遗传关系的变化 这些表型在发育相关的纵向样本中。申请人的主要职业目标是 开发一个研究计划，将复杂的统计遗传学建模方法与 人格、神经认知和成瘾的理论和经验模型，以研究遗传 问题饮酒及相关外化障碍对发育病因学的影响。 具体目标：拟议的项目旨在(1)确定生物贡献和个别基因组区域 影响多个性状及其协变，(2)检验攻击性之间的因果、方向关系， 执行功能、ADHD和饮酒，以及(3)检查在以下三个方面的遗传协变的纵向变化 表型。为了完成拟议的项目，申请人将接受广泛的高级培训 对来自定量和分子领域专家的遗传和表型数据建模的统计方法 遗传学和酒精使用、执行功能和外化障碍病因学。培训将通过以下途径获得 (1)课程作业，(2)出席会议和研讨会，以及(3)与专家顾问会面。 方法：为达到上述目的，申请者将获得相应的攻击性，执行 功能、注意力缺陷多动障碍和酒精使用GWAS汇总统计(发现样本；见Research中的表1 战略部分)以及来自青少年纵向样本的全基因组遗传和表型数据 和年轻人(目标样本)，由Slutske博士(顾问)提供。以下是发现示例数据 将使用收购、分层-连锁不平衡得分回归和GNOVA来识别生物 对每个性状的遗传力及其协变的贡献。接下来，将对这些样本进行荟萃分析以 确定它们共有的变异，然后进行下游分析，以确定共同的生物贡献。下一首, 将利用孟德尔随机化和联合关联方法来确定 表型。最后，将使用OpenMx中的mxGREML来模拟每个 青春期和青春期的表型。 意义：这个项目的结果将增加对导致酒精的遗传因素的理解。 攻击性关系和相关危险因素，重要的是将增加对 这些关系跨越了一个关键的发展时期。这些发现还将代表新的应用 最先进的基因建模技术。

PROJECT SUMMARY/ABSTRACT Long Term Objectives: The overarching goals of this application are to (1) utilize advanced multivariate genome-wide association study (GWAS) approaches to improve current models of the relationship between aggression, alcohol use, executive function, and attention deficit hyperactivity disorder (ADHD), and (2) apply improved genetic liability modeling techniques to the prediction of the changing genetic relationships among these phenotypes in a developmentally relevant longitudinal sample. The applicant’s main career objective is to develop a program of research integrating sophisticated statistical genetics modeling approaches with theoretically and empirically informed models of personality, neurocognition and addiction to investigate genetic influences on the developmental etiology of problematic drinking and related externalizing disorders. Specific Aims: The proposed project aims to (1) Identify biological contributions and individual genomic regions impacting multiple traits and their covariation, (2) Test causal, directional relations between aggression, executive function, ADHD, and alcohol use, and (3) Examine longitudinal changes in genetic covariation between phenotypes. In order to complete the proposed project, the applicant will receive extensive training in advanced statistical methods to model genetic and phenotypic data from experts in the fields of quantitative and molecular genetics and alcohol use, executive function, and externalizing disorder etiology. Training will be obtained via (1) coursework, (2) conference and workshop attendance, and (3) meetings with expert consultants. Method: To complete the abovementioned aims, the applicant will acquire relevant aggression, executive function, ADHD and alcohol use GWAS summary statistics (discovery samples; see Table 1 in Research Strategy section) along with genome-wide genetic and phenotypic data from a longitudinal sample of adolescents and young adults (target sample) provided by Dr. Slutske (Consultant). Following discovery sample data acquisitions, stratified-linkage disequilibrium score regression and GNOVA will be employed to identify biological contributions to the heritability of each trait and their covariation. Next, these samples will be meta-analyzed to identify the variants they share followed by downstream analyses to identify shared biological contributions. Next, Mendelian randomization and joint association methods will be utilized to identify causal relationships among the phenotypes. Finally, mxGREML in OpenMx will be employed to model genetic covariation between each of the phenotypes across adolescence and young adulthood. Significance: Results from this project will increase understanding of genetic factors contributing to the alcohol- aggression relationship and related risk factors, and importantly will increase understanding about changes in these relationships across a critical developmental period. Findings will also represent novel applications of state-of-the-art genetic modeling techniques.