The development of genetically-based pathways underlying problematic alcohol use

酒精使用问题背后基于基因的途径的发展

• 批准号: 10414781
• 负责人: Frances L Wang
• 金额: $ 17.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414781
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Aggressive behavior; Alcohol abuse; Alcohol consumption; Anhedonia; Area; Award; Characteristics; Child; Consultations; Data; Data Set; Development; Dimensions; Distant; Emotions; Environment; Etiology; Family; Female; Frequencies; Fright; Frustration; Functional disorder; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genotype; Growth; Heritability; Impairment; Impulsivity; Individual; Inherited; Intervention; Irritable Mood; Lead; Light; Longitudinal Studies; Measures; Mental Depression; Mentors; Methods; Michigan; Modeling; Outcome; Parents; Pathway interactions; Pattern; Phenotype; Prevention; Prospective cohort; Psychopathology; Quantitative Genetics; Reproducibility; Research; Research Training; Risk; Risk Factors; Sex Differences; Signal Transduction; Societies; Substance Use Disorder; Surveys; Symptoms; TNFSF10 gene; Targeted Research; Temperament; Testing; Time; Training; Universities; Work; alcohol content; alcohol risk; alcohol use disorder; base; cohort; comorbidity; conduct problem; cost; data harmonization; depressive symptoms; deter alcohol use; gene discovery; genetic pedigree; genome-wide; genomic data; improved; individualized medicine; individualized prevention; insight; male; negative affect; novel; open data; population based; precision medicine; programs; relating to nervous system; sex; skills; substance use; trait

PROJECT SUMMARY/ABSTRACT Problematic alcohol use (ALC) has devastating consequences for individuals, families and society. It is imperative to illuminate the poorly understood genetic basis of ALC to improve the precision of prevention and treatment. Research shows that heritable adolescent precursors to ALC are conduct problems (CP), depression (DEP), and particularly their co-occurrence. Moreover, temperament provides important clues to the diverse genetic origins of CP and DEP. This suggests that combinations of CP and DEP symptoms and temperament characteristics may yield novel, genetically-distinct traits that could become new, more precise targets of ALC prevention. The research targets analysis of four prospective cohorts that will be integrated using advanced data harmonization: Adult and Family Development Project (PI: Chassin), Michigan Longitudinal Study (PI: Zucker), Tracking Adolescents’ Individual Lives Survey (PI: Oldehinkel), and Avon Longitudinal Study of Parents and Children (PI: Timpson). Collectively, these datasets provide multigenerational extended pedigrees densely affected with ALC, genomic data, longitudinal data spanning 10+ years, and rich phenotyping of key measures that are similar or identical across cohorts. Aim 1 will examine patterns by which symptoms of CP and DEP and temperament characteristics are inherited, thus identifying highly heritable traits underlying ALC. Aim 2 will employ group-based multi-trajectory modeling of these heritable traits across adolescence (ages 11-18) and relate them to ALC outcomes into adulthood. In Aim 3, sex differences in the multi-trajectory groups and in their associations with ALC will be examined. The complementary research and training aims will be instrumental in launching the candidate’s independent research program on the genetics and development of alcohol use disorder (AUD). The proposed award will provide training in an optimal scientific environment, the University of Pittsburgh, across several key areas: (1) quantitative genetics, large-scale genotypic analysis, genetics of AUD, and other advanced methods with Dr. Bernie Devlin, primary mentor and expert in statistical genetics, and Dr. Arpana Agrawal, consultant and expert in the genetics of AUD; (2) development of AUD and comorbid psychopathology into adulthood with Dr. Brooke Molina, co-mentor and expert in AUD and comorbidity; and (3) data harmonization through consultation with Dr. Patrick Curran, an expert in longitudinal data harmonization. This training will equip the candidate to conduct powerful genetic studies, to take advantage of ever-increasing open data, and to contextualize genetic influences on AUD. With the support of this award, the candidate will gain skills to conduct genetically-informative research that will improve the precision of identification for adolescents at-risk for AUD. This program of research has the potential to advance the field by producing insights into AUD etiology that could eventually inform precision-medicine based prevention.

项目摘要/摘要 有问题的饮酒（ALC）对个人，家庭和社会造成了破坏性的后果。这是 必须阐明ALC的遗传基础知之甚少，以提高预防的精度和 治疗。研究表明，ALC的遗传青春期前体是行为问题（CP），抑郁症 （DEP），尤其是它们的共发生。此外，温度为潜水员提供了重要的线索 CP和DEP的遗传起源。这表明CP和DEP症状和温度的组合 特征可能会产生新颖的，具有遗传学的特征，这些特征可能会成为ALC的新靶标的新的，更精确的靶标 预防。研究目标分析将使用高级数据整合四个前瞻性队列 协调：成人和家庭发展项目（PI：Chassin），密歇根州纵向研究（PI：Zucker）， 跟踪青少年的个人生活调查（PI：Oldehinkel）和Avon纵向研究 儿童（PI：Timpson）。总的来说，这些数据集提供了多代扩展的血统 受ALC，基因组数据，纵向数据跨越10年以上的影响以及关键度量的丰富表型 跨人群相似或相同。 AIM 1将检查CP和DEP的符号以及 气质特征是继承的，从而确定了ALC的基本特征。 AIM 2意志 这些遗传性状的基于员工群体的多区域建模（11-18岁）和 将它们与成年后的ALC结果联系起来。在AIM 3中，多条件组的性别差异及其 将检查与ALC的关联。完整的研究和培训目标将在 启动候选人的独立研究计划，内容涉及饮酒的遗传学和开发 障碍（AUD）。拟议的奖项将在最佳科学环境中提供培训 匹兹堡，在几个关键领域：（1）定量遗传学，大规模基因型分析，AUD的遗传学， 以及统计遗传学的主要心理和专家伯尼·德夫林（Bernie Devlin）博士和其他先进方法，博士 Arpana Agrawal，AUD遗传学的顾问和专家； （2）AUD和合并的开发 精神病理学与澳元和合并症专家布鲁克·莫利纳（Brooke Molina）博士成年； （3） 数据协调通过与纵向数据协调专家Patrick Curran博士进行协商。 该培训将使候选人能够进行强大的遗传研究，以利用不断增长的优势 打开数据，并将遗传影响对AUD的影响进行上下文。在该奖项的支持下，候选人将 提高技能以进行遗传信息研究，以提高识别精度 青少年在风险上供澳元。该研究计划有可能通过产生见解来推进该领域 进入AUD病因，最终可以为基于精密的医学素预防提供信息。