MARC: Genetic Epidemiology of Alcoholism & Comorbidity

描述(由申请者提供)：这是中西部多地点酒精中毒研究中心(MARC)的第一个竞争性续展项目。我们研究的广泛重点是社区(而不是临床确定的)样本中酒精问题和相关共病的病因和过程，重点放在预期的高危、行为和分子遗传学、遗传流行病学和实验角度，并特别关注青少年。MARC的组织形式为：(I)行政核心，在MARC主任Heath、科学与行政联席主任Sher和Bucholz的领导下，负责协调MARC研究项目之间的相互协调，以及与我们由R01资助的更广泛的遗传、预期高风险和人体实验研究组合，以及对MARC研究项目的评估、确定、数据管理和方法支持；(Ii)四项研究；以及(Iii)试点，以促进新酒精研究人员的开发，以及为现有研究人员提供新的方向。研究内容包括四个部分。首先，在人体实验实验室中调查酒精和烟草对酒精效应(姿势不稳定)或烟草效应(生理震颤)敏感性测量的交互影响。其次，使用双胞胎子女范式来调查母亲酗酒的环境后果的影响，包括可能与后代基因相互作用的影响，方法是比较7岁及以上母亲的后代的结果，这些后代要么是酗酒的母亲(遗传风险高，环境风险高)，要么是未受影响的母亲的后代，后者可能有(A)酗酒的同卵双胞胎姐妹(也有高遗传风险，但环境风险降低)，或(B)酗酒的异卵双胞胎姐妹(中等遗传风险，环境风险降低)，或(C)未受影响的双胞胎姐妹(低遗传风险，低环境风险)。第三，通过增加分子遗传成分，扩展4项正在进行的研究，前瞻性地跟踪样本从青春期到年轻成年期，以调查候选基因对风险的发育影响。第四，寻求弥合酒精和烟草共病的流行病学和遗传流行病学研究与人体实验研究之间的差距，通过电子日记评估酒精和烟草并存及其动机后遗症的生态学研究。综合起来，我们希望在多个分析水平上推进关于基因x环境交互作用对酒精中毒风险影响的病因学研究。

DESCRIPTION (provided by applicant): This is the first competing continuation for the multi-site Midwest Alcoholism Research Center (MARC). The broad focus of our research is the etiology and course of alcohol problems and associated comorbidity in community (rather than clinically ascertained) samples, with an emphasis on prospective high-risk, behavioral and molecular genetic, genetic epidemiologic and experimental perspectives, and with a particular focus on adolescents and youth. The MARC is organized as: (i) an Administrative Core, under the leadership of MARC Director Heath and Scientific and Administrative Co-Directors Sher and Bucholz, which is responsible for coordinating MARC-based research projects with each other, and with our broader R01-supported Portfolio of genetic, prospective high-risk and human experimental studies, as well as for assessment, ascertainment, data-management and methodologic support for MARC-based research projects; (ii) four research studies; and (iii) a pilot to facilitate the development of new alcohol researchers, as well as new directions for established investigators. The research studies include four parts. First, investigating in the human experimental laboratory interactive effects of alcohol and tobacco on measures of sensitivity to alcohol effects (postural instability) or tobacco effects (physiologic tremor). Second, using a children-of-twins paradigm to investigate the effects of environmental consequences of maternal alcoholism, including effects that may interact with offspring genotype, by contrasting outcomes in offspring 7 years and older who are either offspring of an alcoholic mother (at high genetic risk, and high environmental risk), or of an unaffected mother who may have (a) a monozygotic twin sister who is alcoholic (also high genetic risk, but reduced environmental risk), or (b) an alcoholic dizygotic twin sister (intermediate genetic risk, reduced environmental risk), or (c) an unaffected twin sister (low genetic and low environmental risk). Third, extending 4 ongoing studies that have followed samples prospectively from adolescence into young adulthood, by adding a molecular genetic component, to investigate the developmental unfolding of candidate gene effects on risk. Fourth, seeking to bridge the gap between epidemiologic and genetic epidemiologic studies of alcohol-tobacco comorbidity, and human experimental studies, as an ecological study of the co-occurrence of alcohol and tobacco use and their motivational sequelae, assessed by electronic diary. Together these are integrated by our desire to advance etiological research on genotype x environment interaction effects on alcoholism risk at multiple levels of analysis.