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，具有巨大的经济成本。酒精障碍是代际遗传的，四分之一的美国儿童受到父母饮酒问题的影响，并伴有相关的精神和身体健康问题，这些问题会持续到成年。预防计划的目标是父母和家庭环境，因为理论上他们在早期饮酒和酒精障碍风险中的作用。“越轨倾向”理论认为，酗酒父母提供了混乱和冲突的家庭环境和缺乏支持、监控和一致纪律的养育方式，这反过来又加剧了“行为可控”对酒精结果的遗传传播脆弱性的影响。然而，需要研究来澄清父母/家庭环境在相关遗传风险背景下的作用。如果做不到这一点，就有可能错误地估计育儿效果，错误地确定干预的最佳内容和受众。一篇使用候选基因的小文献测试了父母教养对遗传风险的调节作用。然而，由于候选基因通常只能解释结果中的少量差异，因此这些研究通常提供的基因-环境相关性测试薄弱，不充分。本R21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，为这个问题引入了一种新的方法。基于理论和研究，我们创建了一个多基因风险评分，以反映多巴胺能、谷氨酸能、gaba能和胆碱能毒蕈碱系统中候选基因的snp控制行为的假定基因组风险。我们使用这个分数来测试父母/家庭环境作为控制行为的假定基因组风险的中介和调节因子。然后，我们添加了一个“经验推导”的多基因风险评分，作为基因-环境相关性的额外测量，解释了养育子女的实质性差异。这个分数由在我们与养育子女进行的关联分析中具有重要意义的SNPs和bb1000个SNPs组成（与成瘾有关，但与控制行为无关，不包括在“理论驱动”组合中）。结合这种“经验推导”的分数作为额外的基因-环境相关性测量，提供了一个更严格的测试，即育儿和家庭环境作为理论驱动的假定基因组风险对控制行为的影响的中介和调节者。该项目的目标将通过对酒精障碍风险代际传递的三代纵向遗传信息研究进行二级数据分析来实现。

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.