Exploring a novel approach to clarify parenting effects on drinking outcomes

描述（由申请人提供）：在美国，过度饮酒是可预防的死亡和残疾的重要原因，经济成本高。酒精障碍是代际传播的，四分之一的美国儿童暴露于父母饮酒问题，伴随着相关的精神和身体健康问题，这些问题一直持续到成年。预防计划针对父母和家庭环境，因为它们在早期饮酒和酒精障碍风险中的理论作用。“越轨倾向”理论认为，酗酒的父母提供了混乱和冲突的家庭环境，缺乏支持，监督和一致的纪律，这反过来又加剧了遗传易感性对酒精结果的影响。如果不这样做，就有可能错误估计养育效果，错误确定干预的最佳内容和受众。一个小的文献使用候选基因测试了父母作为遗传风险的调节剂。然而，由于候选基因通常只能解释结果中的少量差异，这些研究往往提供了弱的，不充分的基因-环境相关性测试。这个R21引入了一种新的方法来解决这个问题，通过创建两个多基因风险评分来提供更强的基因-环境相关性测试。基于理论和研究，我们创建了一个多基因风险评分，以反映在多巴胺能、多巴胺能、GABA能和胆碱能毒蕈碱系统的候选基因的SNP控制下的行为的假定基因组风险。我们用这个分数来测试父母/家庭环境作为一个调解人和一个主持人的假定基因组风险的行为控制。然后，我们添加了一个“衍生的”多基因风险评分作为基因-环境相关性的额外措施，解释了父母的实质性差异。该评分由在我们与父母进行的关联分析中显着的SNP和> 1，200个SNP组成（与成瘾相关，但不特定于控制下的行为，也不包括在“理论驱动”复合物中）。将这种“经验得出的”评分作为额外的基因-环境相关性测量，提供了对养育和家庭环境作为理论驱动的假定基因组风险对行为受控的影响的中介和调节的更严格的测试。项目目标将通过对酒精紊乱风险代际传递的三代纵向遗传信息研究的二级数据分析来实现。 将对两代后代进行分析，以提供内部复制。研究结果将有助于澄清父母和家庭环境在饮酒结果中的作用， 为以家庭为基础的预防计划提出了方向，并为未来研究酒精障碍风险发展中的基因-环境相互作用提供了方法。

DESCRIPTION (provided by applicant): Excessive drinking is an important cause of preventable death and disability in the U.S., with large economic costs. Alcohol disorders are transmitted intergenerationally, and one in four U.S. children is exposed to parent problem drinking, with associated mental and physical health problems that persist into adulthood. Prevention programs have targeted parenting and family environment because of their theoretical roles in early drinking and risk for alcohol disorder. "Deviance proneness" theories posit that alcoholic parents provide disorganized and conflictual family environments and parenting that lacks support, monitoring, and consistent discipline, which, in turn exacerbate the effects of a genetically-transmitted vulnerability to "behavioral under control" on alcohol outcomes However, studies are needed to clarify the role of parenting/family environment in the context of correlated genetic risk. Failing to do so risks mis-estimating parenting effects and mis-identifying the optimal content and audiences for intervention. A small literature using candidate genes has tested parenting as a moderator of genetic risk. However, because candidate genes typically explain only small amounts of variance in outcomes, these studies often provide weak, insufficient tests of gene-environment correlation. This R21 introduces a novel approach to this problem by creating two polygenic risk scores to provide a stronger test of gene-environment correlation. Based on theory and research, we create a polygenic risk score to reflect presumed genomic risk for behavioral under control with SNPs from candidate genes in dopaminergic, glutamatergic, GABAergic, and cholinergic muscarinic systems. We use this score to test parenting/family environment as a mediator and a moderator of presumed genomic risk for behavioral under control. We then add an "empirically-derived" polygenic risk score as an additional measure of gene-environment correlation that explains substantial variance in parenting. This score is composed of SNPs that are significant in association analyses that we conduct with parenting and >1,200 SNPs (relevant to addiction but not specific to behavioral under control and not included in the "theory-driven" composite). Incorporating this "empirically- derived" score as an additional gene-environment correlation measure, provides a more rigorous test of parenting and family environment as mediators and moderators of the effects of theory-driven presumed genomic risk for behavioral under control. The project goals will be accomplished through secondary data analysis of a three-generation, longitudinal, genetically informative, study of the intergenerational transmission of risk for alcohol disorders. Analyses will be conducted for two generations of offspring to provide an internal replication. The results will help to clarify the role of parenting and family environment in drinking outcomes, suggest directions for family-based prevention programs, and provide a method for future studies of gene- environment interplay in the development of risk for alcohol disorder.