Co-Twin Control Analysis of Effects of Alcohol on Brain Morphometry: Disentangling Cause From Consequence

项目总结/摘要 酒精使用障碍（AUDs;酒精滥用和依赖）和有问题的酒精使用相关 在多个功能领域出现严重的负面结果和严重损害，包括 身体健康和死亡率、精神健康、心理社会功能、神经认知缺陷，以及 大脑结构和功能的偏差。然而，绝大多数国家的主要跨部门性质 现有研究的不足意味着这些联系的因果基础仍然不清楚--问题酒精 使用似乎对大脑有神经毒性作用，但大脑偏差反映了前 首先是对有问题的酒精使用的现有责任。二次数据分析奖 旨在通过利用酒精使用和磁共振成像（MRI）数据来解决这个问题， 收集在两个大的，独立的，以人口为基础的，遗传信息的成人样本，从 明尼苏达州双胞胎和家庭研究中心（MCTFR，N = 1152）和人类连接组项目 (HCP，N = 1113）。具体目标1是对现有的 量化酒精使用和脑形态测量学的各种指标之间的关联的经验文献; 我们希望能发现大脑结构和白色物质微观结构的中度到中度群体效应 抑制控制、奖励处理和学习/记忆系统中的偏差。具体目标2 通过应用复杂和创新的定量方法跟踪荟萃分析的结果， MCTFR样本的双胞胎，以获得在因果关系的问题，包括共同双胞胎分析，区分前， 现有的责任，从酒精对大脑的影响，生物识别建模，以分区共享 将家庭责任纳入遗传和共享环境效应，并调整倾向评分以控制 混杂因素不共享的共同双胞胎;我们假设，大脑偏差的基础受损抑制 控制和奖励处理反映了预先存在的负债，而偏离潜在的减值 学习/记忆反映了酒精相关的影响。纳入了更多的女性样本 比通常在酒精研究中检查的更进一步使我们能够检查性别的潜在适度， 具体目标3，特别是假设女性大脑比男性大脑更容易受到 酒精暴露的影响。最后，《具体目标4》是对《公约》中积极发现的复制尝试， 双胞胎及其非双胞胎兄弟姐妹的独立HCP样本。因此，拟议的项目结合了几个 策略，以确保可信的，因果关系的信息，概括性和可重复的结果。结果 对进一步了解有问题的酒精使用的病因和后果具有相当大的潜力， 反过来，指导必要的预防和干预工作，以减少巨大的负面公共卫生 以及酗酒对个人的影响

PROJECT SUMMARY/ABSTRACT Alcohol use disorders (AUDs; alcohol abuse and dependence) and problematic alcohol use are associated with substantial negative outcomes and significant impairment in multiple domains of functioning, including physical health and mortality, psychiatric health, psychosocial functioning, neurocognitive deficits, and deviations in brain structure and functioning. However, the primarily cross-sectional nature of the vast majority of existing research means that the causal basis of these associations remains unclear—problematic alcohol use appears to have neurotoxic effects on the brain, but it is also plausible that brain deviations reflect pre- existing liability toward problematic alcohol use in the first place. The proposed secondary data analysis award aims to address this question by leveraging alcohol use and magnetic resonance imaging (MRI) data already collected in two large, independent, population-based, genetically informative adult samples from the Minnesota Center for Twin and Family Research (MCTFR, N = 1152) and the Human Connectome Project (HCP, N = 1113). Specific Aim 1 is to conduct a comprehensive, meta-analytic synthesis of the existing empirical literature to quantify associations between varied indicators of alcohol use and brain morphometry; we expect to find modest-to-moderate population effects for brain structure and white matter microstructure deviations in systems underlying inhibitory control, reward processing, and learning/memory. Specific Aim 2 follows up on the results of the meta-analysis by applying sophisticated and innovative quantitative methods in the MCTFR sample of twins to get at issues of causality, including co-twin analyses that differentiate pre- existing liability from exposure-related effects of alcohol on the brain, biometric modeling to partition shared familial liability into genetic and shared environmental effects, and propensity score adjustment to control for confounding factors unshared by co-twins; we hypothesize that brain deviations underlying impaired inhibitory control and reward processing reflect pre-existing liability, whereas deviations underlying impaired learning/memory reflect alcohol exposure-related effects. The inclusion of a much larger sample of females than typically examined in alcohol research further allows us to examine potential moderation by sex in Specific Aim 3, specifically the hypothesis that the female brain is more susceptible than the male brain to effects of alcohol exposure. Finally, Specific Aim 4 is a replication attempt of positive findings in the independent HCP sample of twins and their nontwin siblings. Thus, the proposed project combines several strategies to ensure credible, causally informative, generalizable, and reproducible findings. Results have considerable potential to further understanding of the etiology and consequences of problematic alcohol use, and, in turn, guide needed prevention and intervention efforts to reduce the tremendous negative public health and personal implications of alcohol misuse.