Validating Novel Familial Phenotypes of Drug Abuse

描述(由申请人提供)： 这是对RFA-DA-04-005的回应，RFA-DA-04-005要求对描述和评估创新药物滥用表型的研究提出建议，这些表型将提供信息并完善对遗传风险的调查。这一建议的总体目标是使用多代视角和对多个功能领域的广泛评估，系统和准确地开发可为遗传学研究提供信息的家族性sud表型。因此，未来的分子遗传学研究可能会更有成果，如果他们专注于这些明显发展的替代表型，以最大限度地提高它们检测基因的能力。 在从转介的ADHD青少年中确定的家庭背景下，我们将确定哪些临床和功能表型特征在患有肥胖症的受试者中比没有肥胖症的受试者更常见，以及这些特征是否随着时间的推移而稳定。然后我们将检查这些表型是否通过家庭传播，以及这种传播的强度是否与肥胖症有关。我们还将调查肥胖症与共病情绪和反社会障碍之间的家族关联。然后，我们将通过在患有双相情感障碍的青少年家庭中重复这些分析来评估这些发现的特异性。在整个研究过程中，我们将测试性别对这些新表型的表达和熟悉程度的影响。 按照论坛的建议，我们将利用现有的数据来源，这些数据来源将为我们提供充足的统计能力、相当大的成本效益和广泛的概括性。我们将使用几个相同设计的病例对照家族遗传学研究，对被诊断为ADHD或双相情感障碍的年轻人进行研究。所有研究都使用了结构化的精神病学诊断访谈、认知和神经心理测试以及心理社会和全球功能测量来评估先证者及其一级亲属。将采用最先进的统计技术。

DESCRIPTION (provided by applicant): This is a response to RFA-DA-04-005, which requests proposals for studies that describe and evaluate innovative drug abuse phenotypes that will inform and refine investigations into genetic risk. The overall goal of this proposal is to use a multigenerational perspective and an extensive assessment of multiple domains of functioning to systematically and precisely develop familial SUD phenotypes that can be informative to genetic studies. Future molecular genetic studies may thus be more fruitful if they focus on these alternative phenotypes explicitly developed to maximize their power to detect genes. Within the context of families ascertained from a referred ADHD youth, we will determine what clinical and functional phenotypic features are more common among subjects with SUDs than those without SUDs, and whether these features are stable over time. We will then examine whether these phenotypes are transmitted through families and if the strength of this transmission is related to SUDs. We will also investigate the familial association between SUDs and comorbid mood and antisocial disorders. We will then assess the specificity of these findings by replicating these analyses in families ascertained by youth with bipolar disorder. Throughout this research, we will test the effect of gender on the expression and familiality of these novel phenotypes. Following the recommendation of the RFA, we will capitalize on existing data sources that will provide us with ample statistical power, considerable cost-effectiveness and broad generalizability. We will use several identically designed case-control family-genetic studies of youth ascertained by a diagnosis of ADHD or bipolar disorder. All studies used structured psychiatric diagnostic interviews, cognitive and neuropsychological tests and psychosocial and global functioning measures to assess the probands and their first-degree relatives. State of the art statistical techniques will be employed.