Gene-Environment Interplay in Alcoholism

描述(由申请人提供)：这份K05申请请求5年的支持，以允许PI将受保护的时间和精力投入到他的研究和指导计划中，专注于酒精中毒的基因-环境相互作用和风险机制，使他从行政责任的侵占中解放出来。少年辅导组将聘请4名初级教员，作为NIAAA资助的R01调查员，从事以下实质性领域的工作：(1)与父母酗酒有关的子女环境风险和社会情感问题，以及幼儿和学龄前几年的共病；(2)早发性酗酒和其他物质使用的病因，特别侧重于与父母离婚/从未结婚有关的风险机制；(3)酗酒的过渡和青春期至成年期的问题，特别是儿童期攻击创伤的影响；以及(4)个人和子女的结果，以及风险因素，与反复酒后驾车的女性酒精问题的缓解和恢复有关。这些不同的研究领域与PI在(I)女性酗酒和(Ii)酒精中毒风险遗传传播发生的环境背景方面的长期兴趣相匹配。此外，PI将通过R01支持的项目继续他对酒精中毒领域的贡献，这些项目涉及(I)在MOAFTS的30岁时进行随访，这是一组女性同性双胞胎出生队列，从中位数15岁开始跟踪，以确定遗传影响对酒精问题的发生和恢复与持续存在的中介和调节因素；(Ii)继续跟踪澳大利亚双胞胎儿童队列，对比母亲或父亲酗酒(高环境风险，高遗传风险)和仅在父母的MZ同卵双胞胎(降低的环境风险，高遗传风险)或DZ同卵双胞胎(中等遗传风险)和对照中与酗酒有关的结果；以及(Iii)方法贡献和二次数据分析，利用澳大利亚双胞胎登记册和AFMOTS研究的协调评估和关于环境和基因相互作用机制的信息(包括可获得关于4000人的ATR全基因组关联数据)。了解酒精中毒遗传的环境背景，应该既提高对如何识别问题高危人群并对其进行干预的理解，也有助于基因发现。

DESCRIPTION (provided by applicant): This K05 application requests 5 years of support to allow the PI to commit protected time and effort to his research and mentoring program focused on gene-environment interplay and risk-mechanisms in alcoholism, freeing him from the encroachment of administrative responsibilities. The Pi's mentoring will engage 4 junior faculty in the pursuit of independence as NIAAA-funded R01 investigators, in the substantive areas of (i) offspring environmental risks and socioemotional problems associated with parental alcoholism, and comorbidity during the toddler and preschool years, (ii) etiology of very early-onset alcohol and other substance use, with a particular focus on risk-mechanisms associated with parental divorce/never marriage, (iii) transitions in alcohol use and problems from adolescence through young adulthood, particularly the impact of childhood assaultive trauma, and (iv) personal and offspring outcomes, and risk-factors, associated with remission versus recovery of alcohol problems in women with recurrent drunk driving. These diverse research areas are well-matched with the Pi's long-standing interests in (i) alcoholism in women, and (ii) the environmental contexts in which the genetic transmission of alcoholism risk occurs. Additionally, the PI will continue his contributions to the alcoholism field through R01-supported projects which involve (i) follow-up at age 30 of MOAFTS, a birth cohort of female like-sex twin pairs followed from median age 15 to identify mediators and moderators of genetic influences on onset of and recovery from versus persistence in alcohol problems; (ii) continued follow-up of the Australian Children-of-Twins cohorts, contrasting outcomes associated with maternal or paternal alcoholism (high environmental risk, high genetic risk) versus alcoholism only in parent's MZ co-twin (reduced environmental risk, high genetic risk), or DZ co-twin (intermediate genetic risk) and controls; and (iii) methodologic contributions and secondary data-analyses that take advantage of the coordinated assessments, and informativeness about environmental and gene environmental interplay mechanisms, of studies in the Australian twin register and MOAFTS (including the availability of ATR genome-wide association data on 4000 individuals). Understanding environmental contexts for the genetic inheritance of alcoholism should improve both understanding of how to identify and intervene with groups at high-risk for problems, and gene-discovery.