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: 10649419
• 负责人: Kellyn M Spychala
• 金额: $ 4.72万
• 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/10649419
• 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; 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; 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.

项目概要/摘要 长期目标：此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）方法可改善当前之间关系的模型 攻击性、饮酒、执行功能和注意力缺陷多动障碍 (ADHD)，以及 (2) 适用 改进遗传责任建模技术来预测之间不断变化的遗传关系 与发展相关的纵向样本中的这些表型是申请人的主要职业目标。 制定一个研究计划，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，用于研究遗传 对有问题的饮酒和相关外化障碍的发育病因学的影响。 具体目标：拟议项目旨在 (1) 确定生物学贡献和个体基因组区域 影响多个特征及其共变，(2) 测试攻击性之间的因果关系、方向关系， 执行功能、多动症和饮酒，以及（3）检查之间遗传协变的纵向变化 为了完成拟议的项目，申请人将接受广泛的高级培训。 定量和分子领域专家对遗传和表型数据进行建模的统计方法 遗传学和酒精使用、执行功能和外化障碍病因学将通过培训获得。 (1) 课程作业，(2) 会议和研讨会出席情况，以及 (3) 与专家顾问的会议。 方法：为完成上述目标，申请人将获得相关的攻击性、执行力 功能、ADHD 酒精和使用 GWAS 摘要统计（发现样本；参见研究中的表 1） 策略部分）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）提供以下发现样本数据。 将采用收购、分层连锁不平衡评分回归和 GNOVA 来识别生物 接下来，将对这些样本进行荟萃分析以得出每个性状的遗传力及其协变的贡献。 确定它们共享的变异，然后进行下游分析以确定共享的生物学贡献。 将利用孟德尔随机化和联合关联方法来识别之间的因果关系 最后，OpenMx 中的 mxGREML 将用于对每个表型之间的遗传协变进行建模。 青春期和成年早期的表型。 意义：该项目的结果将增进对导致酒精的遗传因素的了解 攻击关系和相关的风险因素，重要的是会增加对变化的理解 这些跨越关键发展时期的关系也将代表新的应用。 最先进的遗传建模技术。