MOLECULAR GENETICS OF HEROIN DEPENDENCE

我们的提案是对NIDA题为“药物成瘾脆弱性的分子遗传学”的申请请求的回应。提出的研究的主要目的是检测一个或多个基因负责遗传传递海洛因依赖。我们的具体目标回应了RFA中指定的目标：1)收集和临床表征一个大的兄弟姐妹对样本，具有足够的统计能力，以确定可能含有赋予海洛因依赖易感性的位点的基因组区域；2)进行全基因组扫描，建立这些基因座的染色体定位；3)从全基因组扫描中跟踪感兴趣的区域并评估候选基因；4)使临床和基因型数据迅速提供给科学界的其他研究人员。为了实现我们的目标，我们与中国云南省的两位精神病学家建立了合作关系。这个省毗邻“金三角”——世界上大部分海洛因的来源——有一个全面的药物滥用登记系统，我们的同事可以进入。登记在册的有大约3万名海洛因成瘾者，我们的中国合作者云南药物滥用研究所所长很容易找到他们。我们将从1000对有DSM-IV定义的海洛因依赖的兄弟姐妹以及他们的父母和其他受影响和未受影响的兄弟姐妹中收集血液和诊断信息（使用结构化诊断访谈）。血液样本将被送到科里尔实验室的细胞库，用于培养淋巴母细胞细胞系。我们将与华盛顿大学的一位同事合作，使用平均间隔10厘米的350个标记完成基因组扫描。基因型和临床数据将使用数据库软件输入。我们将使用Lander和Kruglyak的指导方针进行多点联动分析，以断言统计显著性。我们将用一组更密集的标记物跟踪感兴趣的区域，并评估候选基因。所有临床数据将在资助期结束时提供给科学界。所有基因型将在产生后一年提供，但不迟于资助期结束后一年。我们正在使用RO1机制提交此提案。

Our proposal is a response to NIDA's Request for Applications entitled `Molecular Genetics of Drug Addiction Vulnerability. The main goal of the proposed study is to detect one or more genes responsible for the genetic transmission of heroin dependence. Our Specific Aims respond to those specified in the RFA: 1) To collect and clinically characterize a large sib-pair sample with adequate statistical power for identifying genomic regions that may harbor loci conferring susceptibility to heroin dependence; 2) To conduct a whole-genome scan to establish the chromosomal localization of such loci; 3) To follow-up regions of interest from the whole-genome scan and evaluate candidate genes; and 4) To make the clinical and genotypic data quickly available to other investigators in the scientific community. To accomplish our aims, we have established a collaboration with two psychiatrists in Yunnan Province, China. This province, which borders the "Golden Triangle" -- the source of much of the world's heroin -- has a comprehensive drug abuse registration system to which our colleagues have access. About 30,000 heroin addicts are in the registry and can be easily located by our Chinese collaborator, the Director of the Yunnan Institute for Drug Abuse. We will collect blood and diagnostic information (using a structured diagnostic interview) from 1000 sib-pairs having DSM-IV defined heroin dependence as well as from their parents and other affected and unaffected siblings. Blood samples will be sent to a cell repository at Coriell Laboratories for creation of lymphoblastoid cell lines. In collaboration with a colleague at Washington University, we will complete a genome scan using 350 markers spaced at an average of 10 cM intervals. Genotype and clinical data will be entered using database software. We will conduct a multipoint linkage analysis using the guidelines of Lander and Kruglyak to assert statistical significance. We will follow-up regions of interest with a denser set of markers and evaluate candidate genes. All clinical data will be made available to the scientific community by the end of the funding period. All genotypes will be available one year after they are generated, but no later than a year after the end of the funding period. We are submitting this proposal using the RO1 mechanism.