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

饮酒、攻击性、执行功能和多动症之间的关系：基因分析

• 批准号: 10387890
• 负责人: Kellyn M Spychala
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387890
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Age; Aggressive behavior; Alcohol abuse; Alcohol consumption; Alcohols; Attention; Attention deficit hyperactivity disorder; Biological; Development; Diagnosis; Diagnostic; Disease; Distal; Educational workshop; Etiology; Executive Dysfunction; Frequencies; Genes; Genetic; Genetic Models; Genomic Segment; Genomics; Goals; Heavy Drinking; Heritability; Immune system; Impairment; Individual; Interpersonal Violence; Intoxication; Joints; Knowledge; Linkage Disequilibrium; Measures; Mendelian randomization; Meta-Analysis; Methods; Modeling; Molecular Genetics; Mutation; Neurocognition; Pathway interactions; Personality; Phenotype; Physical aggression; Prefrontal Cortex; Prevalence; Probability; Public Health; Quantitative Genetics; Research; Risk Factors; Sampling; Short-Term Memory; Statistical Methods; Suggestion; Techniques; Testing; Time; Tissues; Training; Variant; addiction; age related; alcohol use disorder; base; career; chronic alcohol ingestion; cognitive function; cost; critical developmental period; data acquisition; design; drinking; early adolescence; emerging adult; executive function; external ear auricle; genetic analysis; genetic approach; genome wide association study; genome-wide; improved; meetings; novel; perpetrators; phenotypic data; programs; statistics; symposium; tool; trait; violent crime; whole genome; young adult

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.

项目总结/摘要 长期目标：该应用程序的总体目标是（1）利用先进的多元 全基因组关联研究（GWAS）的方法，以改善目前的模型之间的关系， 攻击，酒精使用，执行功能和注意缺陷多动障碍（ADHD），和（2）适用于 改进的遗传易感性建模技术，以预测 这些表型在发育相关的纵向样本。申请人的主要职业目标是 制定一项研究计划，将复杂的统计遗传学建模方法与 用于研究遗传的人格、神经认知和成瘾的理论和经验模型 对问题性饮酒和相关外化障碍的发展病因学的影响。 具体目标：拟议的项目旨在（1）确定生物贡献和单个基因组区域 影响多个特征及其协变，（2）测试攻击性之间的因果关系，方向关系， 执行功能，多动症，和酒精的使用，（3）检查纵向变化之间的遗传协变 表型为了完成拟议的项目，申请人将接受高级培训， 统计学方法来模拟来自定量和分子生物学领域专家的遗传和表型数据， 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 (1)课程作业，（2）出席会议和讲习班，以及（3）与专家顾问的会议。 方法：为了完成上述目标，申请人将获得相关的攻击性，执行性 功能、ADHD和酒精使用GWAS汇总统计（发现样本;见研究中的表1 策略部分）沿着的是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。发现示例数据之后 收集，分层连锁不平衡评分回归和GNOVA将被用来确定生物 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， 确定它们共有的变异，然后进行下游分析，以确定共有的生物学贡献。接下来， 孟德尔随机化和联合关联方法将用于确定因果关系， 表型最后，将采用OpenMx中的mxGREML来模拟以下每一个之间的遗传协变： 青春期和青年期的表型。 意义：该项目的结果将增加对导致酒精中毒的遗传因素的理解。 攻击关系和相关的危险因素，重要的是将增加对变化的了解， 这些关系跨越了一个关键的发展时期。研究结果也将代表新的应用， 最先进的基因建模技术