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

项目摘要/摘要 酒精使用障碍(AUDS；酒精滥用和依赖)与有问题的酒精使用有关 在多个功能领域产生重大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，绝大多数人的主要横截面性质 现有的研究表明，这些联系的因果基础仍然不清楚--有问题的酒精 使用似乎对大脑有神经毒性影响，但也有可能大脑偏离反映了前 首先是对有问题的酒精使用的现有责任。拟议的二级数据分析奖 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 收集了两个大的、独立的、基于人群的、具有遗传信息的成人样本，这些样本来自 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 量化酒精使用的不同指标和脑形态测量之间的关联的经验性文献； 我们期望发现对大脑结构和脑白质微结构的适度到中度的群体效应 抑制控制、奖赏处理和学习/记忆基础系统的偏差。具体目标2 通过应用复杂和创新的量化方法对荟萃分析的结果进行跟踪 MCTFR双胞胎样本以获得因果关系问题，包括区分前-双胞胎的同卵双胞胎分析 酒精对大脑暴露相关影响的现有责任，从生物识别建模到分区共享 将家庭责任转化为遗传和共享环境影响，并对倾向得分进行调整以控制 同卵双胞胎没有共有的混杂因素；我们假设大脑偏差是抑制功能受损的基础 控制和报酬处理反映了先前存在的负债，而潜在的偏差则减值 学习/记忆反映了酒精暴露的相关影响。纳入了更大规模的女性样本 比通常在酒精研究中检查的更进一步允许我们检查潜在的性别节制 具体目标3，具体地说，即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是复制在 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 确保可信、因果信息、可推广和可重复性的研究结果的策略。结果是 在进一步了解问题饮酒的原因和后果方面有相当大的潜力， 并反过来指导所需的预防和干预努力，以减少对公共卫生的巨大负面影响 以及酒精滥用对个人的影响。

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.