Modeling poly-genomic risk in the relationship between brain structure and alcohol involvement from adolescence through adulthood

对从青春期到成年期大脑结构与酒精参与之间关系的多基因组风险进行建模

• 批准号: 10013119
• 负责人: RYAN H BOGDAN
• 金额: $ 14.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013119
• 关键词: Accounting; Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Alcohol Phenotype; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Atrophic; Attenuated; Autopsy; Behavior; Biosensor; Brain; Cessation of life; Cognition; Communities; Cues; Data; Development; Education; Emotional; Emotions; Esthesia; Etiology; European; Future; Gene Expression; Genomics; Heavy Drinking; Impulsivity; Individual; Individual Differences; Longitudinal Studies; Maintenance; Manuscripts; Mediating; Memory; Modeling; Not Hispanic or Latino; Pattern; Phenotype; Policies; Predisposing Factor; Predisposition; Prevention; Research; Rewards; Risk; Risk Factors; Risk-Taking; Sample Size; Series; Sleep; Structure; Testing; Time; Trauma; Youth; addiction; alcohol consequences; alcohol effect; alcohol exposure; alcohol involvement; alcohol risk; alcohol use disorder; alcohol use initiation; association cortex; base; binge drinking; burden of illness; cognitive control; cognitive reappraisal; cohort; cost; data sharing; database of Genotypes and Phenotypes; disease classification; drinking; drinking onset; early alcohol use; emerging adult; emotion regulation; gene discovery; genome wide association study; gray matter; indexing; innovation; interest; multimodality; negative affect; neurodevelopment; neuroimaging; neurotoxic; polygenic risk score; preventable death; prospective; relating to nervous system; social; socioeconomics; theories; underage drinking; young adult

PROJECT SUMMARY/ABSTRACT Alcohol use is associated with significant personal and socioeconomic costs (accounting for more than 5% of global disease burden as well as worldwide deaths). Alcohol use initiation, progression to heavy episodic drinking, and early onset alcohol use disorder commonly emerge during adolescence and young adulthood. This developmental period of risk is theorized to result from typical patterns of regionally asynchronous brain maturation (i.e., rapid and early development of limbic regions alongside relatively immature prefrontal and multimodal association cortices) resulting in a diminished ability to suppress inappropriate emotions, desires, and actions when salient environmental cues are present. During later young adulthood the stabilization, reduction, or desistance of heavy use typically occurs alongside maturing cognitive control and emotional regulation abilities coinciding with cortical development. Brain maturation may also be influenced by alcohol use. However, whether alcohol use alters brain maturation and/or results from individual differences in neural development attributable to predipsositional genomic background is unclear and can only be addressed by genomically-informed longitudinal research with extensive alcohol phenotyping. In this 2-year R21, we propose to add genome-wide association study (GWAS) content to 2 longitudinal neuroimaging studies of adolescents and young adults (n=696; spanning ages 12-33 with annual neuroimaging and biannual alcohol characterization) to examine whether brain changes during adolescence and young adulthood associated with alcohol use may represent polygenic risk factors and/or represent consequences of heavy alcohol exposure. Disentangling the contributions of predisposing factors from consequences of alcohol on structural brain trajectories will inform our etiologic understanding of alcohol use during adolescence and young adulthood that could contribute to alcohol- related policy, education, nosology, prevention, and treatment. Primary deliverables from this project will be manuscripts examining whether polygenic propensity to alcohol use, as well as risk for impulsivity and negative affect and deficits in cognition, modify trajectories of brain maturation and further alter the course of youth alcohol engagement. Further, due to the extensive scope of longitudinal data available in these studies (e.g., other neural phenotypes, psychiatric, sleep, trauma, biosensor assessments), the addition of GWAS data will provide benefits to the broader research community through data sharing (e.g., dbGaP) and contribute to consortia-based gene discovery efforts (e.g., ENIGMA, PGC).

项目概要/摘要 饮酒与巨大的个人和社会经济成本相关（占总成本的 5% 以上） 全球疾病负担以及全球死亡人数）。开始饮酒，进展为严重发作性饮酒 饮酒和早发性酒精使用障碍通常出现在青春期和成年早期。这 理论上，风险发育期是由区域异步大脑的典型模式引起的 成熟（即边缘区域的快速和早期发育以及相对不成熟的前额叶和 多模式关联皮层）导致抑制不适当情绪、欲望、 以及出现显着环境线索时采取的行动。在成年后期的稳定时期， 减少或停止大量使用通常伴随着成熟的认知控制和情绪 调节能力与皮质发育相一致。大脑成熟也可能受到酒精的影响 使用。然而，饮酒是否会改变大脑成熟和/或神经元个体差异的结果 归因于预倾向基因组背景的发育尚不清楚，只能通过以下方法解决 具有广泛酒精表型分析的基因组纵向研究。在这个为期 2 年的 R21 中，我们建议 将全基因组关联研究 (GWAS) 内容添加到 2 项青少年纵向神经影像研究中 和年轻人（n=696；年龄跨度为 12-33 岁，每年进行神经影像检查和每年两次酒精特征分析） 研究青春期和成年早期与饮酒相关的大脑变化是否可能 代表多基因风险因素和/或代表重度酒精暴露的后果。解开 酒精对大脑结构轨迹影响的诱发因素的贡献将告诉我们 对青春期和青年期饮酒的病因学了解可能会导致酗酒 相关政策、教育、疾病学、预防和治疗。该项目的主要交付成果将是 研究是否存在多基因饮酒倾向以及冲动和消极风险的手稿 影响和认知缺陷，改变大脑成熟的轨迹，并进一步改变青少年酗酒的过程 订婚。此外，由于这些研究中可用的纵向数据范围广泛（例如，其他神经网络 表型、精神、睡眠、创伤、生物传感器评估），添加 GWAS 数据将带来好处 通过数据共享（例如 dbGaP）向更广泛的研究界提供帮助，并为基于联盟的基因做出贡献 发现工作（例如 ENIGMA、PGC）。