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.

项目概要/摘要 酗酒问题 (ALC) 会给个人、家庭和社会带来毁灭性后果。 当务之急是阐明人们对 ALC 知之甚少的遗传基础，以提高预防和预防的准确性。 研究表明，ALC 的遗传性青少年前兆是品行问题 (CP)、抑郁症。 （DEP），尤其是它们的共现，气质为多样性提供了重要线索。 CP 和 DEP 的遗传起源 这表明 CP 和 DEP 症状和气质的组合。 特征可能会产生新颖的、遗传上独特的性状，这些性状可能成为 ALC 新的、更精确的目标 该研究的目标是对四个前瞻性队列进行分析，这些队列将使用先进的数据进行整合。 协调：成人和家庭发展项目（PI：Chassin）、密歇根纵向研究（PI：Zucker）、 跟踪青少年的个人生活调查（PI：奥尔德辛克尔），以及雅芳父母和青少年的纵向研究 儿童（PI：Timpson）总的来说，这些数据集提供了密集的多代扩展谱系。 受 ALC、基因组数据、跨越 10 年以上的纵向数据以及关键指标的丰富表型影响 目标 1 将检查 CP 和 DEP 症状的模式。 气质特征是遗传的，因此 ALC 目标 2 将识别高度遗传的特征。 对整个青春期（11-18 岁）的这些遗传特征采用基于群体的多轨迹建模 在目标 3 中，多轨迹组及其性别差异与成年后的 ALC 结局相关。 将审查与 ALC 的关联，互补的研究和培训目标将有助于 启动候选人关于酒精使用的遗传学和发展的独立研究计划 拟议的奖项将在最佳科学环境中提供培训，大学。 匹兹堡，跨越几个关键领域：（1）定量遗传学、大规模基因型分析、AUD 遗传学、 以及统计遗传学主要导师和专家 Bernie Devlin 博士和 Dr. Bernie Devlin 博士的指导和其他先进方法。 Arpana Agrawal，AUD 遗传学顾问和专家 (2) AUD 和合并症的发展； 与 AUD 和合并症领域的共同导师兼专家布鲁克·莫利纳 (Brooke Molina) 博士一起研究成年期的精神病理学；以及 (3) 通过咨询纵向数据协调专家 Patrick Curran 博士来协调数据。 该培训将使候选人能够进行强大的基因研究，以利用不断增加的优势 开放数据，并了解遗传对澳元的影响。在该奖项的支持下，候选人将 获得进行遗传信息研究的技能，这将提高识别的精确度 该研究项目有可能通过产生见解来推动该领域的发展。 研究 AUD 病因学，最终可以为基于精准医学的预防提供信息。