Human Genetics of Drug-Abuse Related Phenotypes

描述（由申请人提供）： K 02独立科学家职业发展奖约瑟夫F。Cubells，医学博士，博士本提案寻求支持候选人的继续发展，作为一个研究精神病学家专门从事人类遗传学的药物滥用相关表型。组织研究计划和职业计划的首要假设是，特定位点的序列变异将对特定的药物滥用相关表型产生可测量的影响。这一假设是基于识别和表征适当的表型的重要性，这将反映一个或几个具有高突变率的基因的影响。研究计划中提出了三个项目。项目1，这是正在进行中，是候选人的R 01资助的研究可卡因引起的精神病（DA 12422）的人类遗传学。该项目试图从可卡因依赖的无关个体和含有可卡因依赖先证者的家庭三人组中收集DNA样本;这些先证者被仔细描述可卡因诱导的精神病症状，轴1物质滥用和精神病诊断，以及儿茶酚胺合成酶多巴胺β-羟化酶的血浆水平。项目2将在项目1的基础上，研究邻近多态性之间的连锁不平衡如何影响数量性状的表型变异。项目3将阐明尼古丁依赖相关表型的遗传影响，通过检查在COMT基因座的功能变异对人类神经认知功能和声学惊吓反应的影响，在吸烟和不吸烟的受试者，有和没有精神分裂症。职业发展计划将需要与耶鲁大学和康涅狄格大学的同事合作，他们的专业知识范围从复杂表型的评估到分子遗传学，再到统计遗传学。此外，候选人计划具体的课程，无论是在耶鲁大学，并在校外网站，以加强他在分子，统计和临床遗传学的专业知识。后一个目标将由候选人指导新成立的耶鲁人类行为遗传学诊所来实现，该诊所为遗传疾病患者提供精神病和药物滥用服务。

DESCRIPTION (provided by applicant): K02 Independent Scientist Career Development Award for Joseph F. Cubells,MD, PhD This proposal seeks support for the candidate's continued development as a research psychiatrist specializing in human genetics of drug-abuse-related phenotypes. The overarching hypothesis organizing both the Research Plan and the Career Plan is that sequence variation at specific loci will exert measurable effects on specific drug-abuse-related phenotypes. This hypothesis is predicated on the importance of identifying and characterizing appropriate phenotypes, which will reflect the effects of one or a few genes with high penetrance. Three projects are proposed in the Research Plan. Project 1, which is well under way, is the candidate's R01-funded research on the human genetics of cocaine-induced psychosis (DA 12422). The project seeks to collect DNA samples from unrelated individuals with cocaine dependence, and from family trios containing cocaine-dependent probands; these probands are carefully characterized for cocaine-induced psychotic symptoms, and for axis-1 substance-abuse and psychiatric diagnoses, as well as for plasma levels of the catecholamine-synthetic enzyme dopamine beta-hydroxylase. Project 2 will build on work accomplished in Project 1, to examine how linkage disequilbrium among nearby polymorphisms influences phenotypic variation in quantitative traits. Project 3 will elucidate genetic influences on nicotine-dependence-related phenotypes by examining the influence of functional variation at the COMT locus on human neurocognitive function and acoustic startle responses in smoking and nonsmoking subjects, with and without schizophrenia. The Career Development Plan will entail collaboration with colleagues at Yale University and the University of Connecticut, whose expertises range from evaluation of complex phenotypes, to molecular genetics, to statistical genetics. In addition, the candidate plans specific coursework, both at Yale, and at off-campus sites, to strengthen his expertise in a both molecular, statistical and clinical genetics. The latter goal will be accomplished by the candidate directing the newly-established Yale Human Behavioral Genetics Clinic, which offers psychiatric and substance-abuse services to patients with genetic illnesses.