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

项目摘要/摘要 饮酒与巨大的个人和社会经济成本有关(占5%以上 全球疾病负担以及世界范围内的死亡)。酒精使用开始，进展为重度发作 饮酒和早发性酒精使用障碍通常出现在青春期和青年时期。这 从理论上讲，风险发育期是由典型的区域不同步大脑模式造成的 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 多模式联合皮质)导致抑制不适当情绪、欲望、 以及当出现显著的环境线索时采取的行动。在成年后的稳定阶段， 减少或停止大量使用通常伴随着成熟的认知控制和情绪 调节能力与大脑皮层发育相一致。酒精也可能影响大脑的成熟。 使用。然而，饮酒是否会改变大脑的成熟和/或导致神经的个体差异 可归因于先兆基因组背景的发育尚不清楚，只能通过 广泛酒精表型的基因信息纵向研究。在此2年制R21中，我们建议 在2项青少年纵向神经影像研究中增加全基因组关联研究(GWAS)的内容 和年轻人(n=696；年龄12-33岁，每年一次的神经成像和一年两次的酒精特征) 研究青春期和青春期的大脑变化是否与饮酒有关 代表多基因风险因素和/或代表重酒暴露的后果。解开纠缠的 酒精后果中的易感因素对大脑结构轨迹的贡献将告诉我们 青春期和青春期饮酒可能导致饮酒的病因学理解-- 相关政策、教育、病因学、预防和治疗。该项目的主要交付成果将是 研究多基因饮酒倾向以及冲动和消极风险的手稿 影响和缺陷认知，改变大脑成熟的轨迹，并进一步改变青年酒精的进程 订婚。此外，由于在这些研究中可获得的纵向数据的广泛范围(例如，其他神经 表型、精神病学、睡眠、创伤、生物传感器评估)，增加GWAS数据将提供好处 通过数据共享(例如，DBGaP)提供给更广泛的研究社区，并为基于联盟的基因做出贡献 发现努力(例如，谜团、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).