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

项目总结/摘要 酒精使用与重大的个人和社会经济成本有关（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，进展为重度发作性 饮酒和早发性酒精使用障碍通常出现在青春期和青年期。这 风险的发展期理论上是由区域异步大脑的典型模式造成的 成熟（即，边缘区的快速和早期发展，与相对不成熟的前额叶和 多模式联合皮层），导致抑制不适当的情绪，欲望， 和行动时，突出的环境线索存在。在后来的青年期， 减少或停止大量使用通常伴随着成熟的认知控制和情绪控制。 调节能力与皮质发育一致。大脑的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的成熟和/或导致神经系统的个体差异， 归因于predipsositional基因组背景的发展尚不清楚，只能通过以下方法来解决： 基因组信息的纵向研究与广泛的酒精表型。在这两年的R21中，我们建议 在2项青少年纵向神经影像学研究中增加全基因组关联研究（GWAS）内容 和年轻成人（n=696;年龄跨度为12-33岁，每年进行一次神经影像学检查，每两年进行一次酒精表征） 研究青春期和青年期与饮酒有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 酒精对结构性大脑轨迹的影响的诱发因素的贡献将告诉我们， 对青少年和青年期饮酒的病因学理解可能导致酒精- 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 研究多基因酒精使用倾向，以及冲动和消极的风险 影响和认知缺陷，改变大脑成熟的轨迹，并进一步改变青年酒精的过程 订婚此外，由于这些研究中可获得的纵向数据范围广泛（例如，其他神经 表型、精神病、睡眠、创伤、生物传感器评估），增加GWAS数据将带来益处 通过数据共享向更广泛的研究界提供信息（例如，dbGaP）并有助于基于聚生体的基因 发现努力（例如，ENIGMA，PGC）。

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).