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。酒精障碍是代际传播的，每四个美国儿童中就有一个接触到父母问题饮酒，并伴随着相关的心理和身体健康问题，这些问题一直持续到成年。预防计划针对的是育儿和家庭环境，因为它们在早期饮酒和酒精障碍风险方面扮演着理论上的角色。“偏执倾向”理论认为，酗酒的父母提供了混乱和冲突的家庭环境，以及缺乏支持、监督和一致的纪律的养育方式，这反过来又加剧了通过基因传播的“控制下的行为”的脆弱性对酒精结果的影响。然而，需要研究来澄清父母养育/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，可能会错误估计育儿效果，并错误地识别最适合干预的内容和受众。一份使用候选基因的小型文献已经测试了父母教养方式是遗传风险的调节因素。然而，由于候选基因通常只能解释结果中的少量差异，这些研究往往对基因与环境的相关性提供了薄弱的、不充分的测试。R21通过创建两个多基因风险分数来为这个问题引入一种新的方法，以提供更强的基因-环境相关性测试。在理论和研究的基础上，我们创建了一个多基因风险评分，以反映在多巴胺、谷氨酸、GABA和胆碱能毒碱系统候选基因的SNPs控制下的行为的假定基因组风险。我们使用这个分数来测试父母/家庭环境作为控制下行为的假定基因组风险的中介和调节因素。然后，我们增加了一个“经验性的”多基因风险得分，作为基因-环境相关性的额外测量，解释了父母养育方式的显著差异。这一得分由在我们对父母教养方式进行的关联分析中具有重要意义的SNPs和1200个SNPs组成(与成瘾有关，但不特定于受控制的行为，也不包括在“理论驱动”的组合中)。将这一“经验式”得分作为额外的基因-环境相关性测量，提供了一种更严格的父母养育和家庭环境测试，作为理论驱动的假定基因组风险对受控行为的影响的中介和调节因素。该项目的目标将通过对酒精障碍风险代际传播的三代、纵向、遗传信息性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。这一结果将有助于阐明父母教养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供方向，并为未来研究酒精障碍风险的基因-环境相互作用提供一种方法。

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.