Human Genetics of Drug-Abuse Related Phenotypes

描述(由申请人提供)： K02授予约瑟夫·F·库贝尔医学博士的独立科学家职业发展奖这项提议寻求支持候选人继续发展成为一名专门研究与药物滥用相关的表型的人类遗传学的精神病学家。组织研究计划和职业计划的首要假设是，特定基因座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表型的重要性，这将反映一个或几个具有高外显性的基因的影响。研究计划中提出了三个项目。正在进行中的项目1是候选人由R01资助的可卡因诱发精神病的人类遗传学研究(DA 12422)。该项目寻求从无血缘关系的可卡因依赖个人和包含可卡因依赖先证者的家庭三人身上收集DNA样本；这些先证者被仔细描述可卡因引起的精神症状、Axis-1药物滥用和精神诊断，以及血浆中儿茶酚胺合成酶多巴胺β-羟基酶的水平。项目2将以项目1中已完成的工作为基础，研究邻近多态之间的连锁不平衡如何影响数量性状的表型变异。项目3将通过研究COMT基因功能变异对吸烟者和非吸烟者的神经认知功能和听觉惊吓反应的影响，阐明基因对尼古丁依赖相关表型的影响，无论是否患有精神分裂症。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，这两所大学的专业范围从复杂表型评估到分子遗传学，再到统计遗传学。此外，候选人还计划在耶鲁大学和校外地点进行具体的课程学习，以加强他在分子、统计学和临床遗传学方面的专业知识。后一个目标将通过领导新成立的耶鲁人类行为遗传学诊所的候选人来实现，该诊所为遗传病患者提供精神和物质滥用服务。

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.