Gene Environment in Outcomes of Offspring of Twins with Substance Use Disorders

描述（由申请人提供）：本续期申请的目的是继续我们的双胞胎后代（OOT）研究839名后代的物质使用障碍（SUD）的发展和过程，这些后代由于其双胞胎父亲及其同卵双胞胎的SUD状况而处于不同水平的环境和遗传风险。我们的OOT设计在区分4组后代方面是独特的：(1)父亲有非法药物依赖史，有或没有酒精依赖史（SUD）的后代具有高遗传和高环境风险（HG-HE）；(2)未患病父亲的后代遗传风险高，但环境风险低（由于没有患病父亲的养育环境-“HG-LE”）；(3) DZ双胞患有SUD/AD的未受影响父亲的后代遗传风险为中等，环境风险为低（MG-LE）；(4)未患病男性（无SUD）与未患病双胞胎的后代具有低遗传和低环境风险（“LG-LE”）。在第一个资助期间，对父母（仅在T1）和子女（在T1和T2，大约相隔2年）进行了全面的精神病学诊断访谈。在我们的第一个拨款期间，我们已经成功地招募和评估了所需的样本，并且紧急发现为更新申请提供了基础。对基线数据的分析表明，高遗传风险有很强的影响。与MG和LG风险后代相比，无论环境风险水平如何，HG后代明显更有可能出现DSM-IV大麻滥用/依赖。基线数据的分析也表明，在调整遗传因素后，特定的环境变量对后代SUD有影响。亲密的亲子关系和兄弟姐妹关系具有保护作用，而如果他们的兄弟姐妹和同龄人吸毒、酗酒和吸烟，他们的后代患SUD的风险就会增加。心理创伤和共病精神病理也被研究作为遗传和家庭环境影响的中介。在我们的下一个资助期，我们建议对子女（T1时平均年龄22岁）进行第三次（T3）和第四次（T4）评估，因为他们已经进入了二十五六岁。这一时期被称为“新成年期”，是物质使用介入、缓解和持续过渡的高峰期。必须进行这些额外的评估，以表征SUD的发展过程，并测试与青年人结局的中介和调节相关的关键假设。此外，我们的姊妹项目“酗酒双胞胎的孩子”（COAT）目前正在实地进行第三和第四次后续工作。该应用将允许继续对COAT和TAP数据进行补充分析，以阐明遗传、饲养环境和特定成人心理社会领域在SUD病因学中的复杂相互作用。

DESCRIPTION (provided by applicant): The purpose of this renewal application is to continue our Offspring-of-Twins (OOT) study of the development and course of substance use disorder (SUD) in 839 offspring who are at different levels of environmental and genetic risks by virtue of the SUD status of their twin-father and that of his co-twin. Our OOT design is unique in distinguishing 4 groups of offspring: (1) Offspring whose fathers have a history of illicit drug dependence, with or without a history of alcohol dependence (SUD) are at both High Genetic and High Environmental risk ("HG-HE"); (2) Offspring of unaffected fathers whose cotwin has a history of SUD are at High Genetic but Low Environmental risk (by virtue of a rearing environment without an affected father - "HG-LE"); (3) Offspring of unaffected fathers whose DZ cotwin has SUD/AD are at Moderate Genetic risk and Low Environmental risk ("MG-LE"); (4) Offspring of unaffected men (no SUD) with unaffected cotwins are at Low Genetic and Low Environmental risk ("LG-LE"). During the first funding period, comprehensive psychiatric diagnostic interviews were administered to parents (at T1 only) and to offspring (at T1 and T2, approximately 2 years apart). We have been successful in recruiting and assessing the needed sample during our first grant period, and emergent findings provide the foundation on which this renewal application is based. Analyses of baseline data indicate a strong effect of high genetic risk. HG offspring are significantly more likely to have DSM-IV cannabis abuse/dependence regardless of level of environmental risk as compared to MG and LG risk offspring. Analyses of baseline data also indicate that specific environmental variables contribute to offspring SUD after adjusting for genetic factors. Close parent- offspring and sibling relationships are protective, while offspring are at increased risk for SUD if their siblings and peers use drugs, alcohol and smoke. Psychological trauma and co-morbid psychopathology have also been investigated as mediators of the genetic and family environmental influences. During our next grant period, we propose a 3rd (T3) and 4th (T4) assessment of the offspring (on average age 22 at T1) as they age into their mid to late twenties. This period of life, known as "emerging adulthood," is a peak period for transitions in substance use involvement, remission and persistence. It is essential that these additional assessments be conducted so that the developmental course of SUD can be characterized and key hypotheses related to mediation and moderation of young adult outcomes tested. In addition, our sister project, the Children of Alcoholic Twins (COAT) is currently in the field for a 3rd and 4th follow-up. This application will permit continued complementary analyses of the COAT and TAP data to elucidate the complex interplay of genetic, rearing environment and specified adult psychosocial domains in the etiology of SUD.