MOLECULAR GENETICS OF HEROIN DEPENDENCE

我们的建议是对NIDA提出的题为‘药物成瘾脆弱性的分子遗传学’的申请的回应。这项拟议研究的主要目标是检测导致海洛因依赖遗传传播的一个或多个基因。我们的具体目标是响应RFA中指定的目标：1)收集具有足够统计能力的大同胞对样本并进行临床鉴定，以确定可能包含海洛因依赖易感性基因座的基因组区域；2)进行全基因组扫描，以确定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；以及4)使临床和基因分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，我们与云南省的两位精神病学家中国建立了合作关系。该省毗邻“金三角”--世界上大部分海洛因的来源地--有一个全面的药物滥用登记系统，我们的同事们都可以使用。登记在册的海洛因成瘾者约有30,000人，我们的中方合作者、云南省毒品滥用研究所所长很容易找到这些人。我们将从1000对被DSM-IV定义为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那里收集血液和诊断信息(使用结构化的诊断性访谈)。血液样本将被送往科里尔实验室的细胞库，用于建立淋巴母细胞系。与华盛顿大学的一位同事合作，我们将使用350个平均间隔10厘米的标记完成基因组扫描。将使用数据库软件输入基因和临床数据。我们将使用兰德和克鲁格拉克的准则进行多点连锁分析，以确定统计意义。我们将用一组更密集的标记来跟踪感兴趣的区域，并评估候选基因。所有临床数据将在资助期结束前提供给科学界。所有基因类型将在产生后一年内可用，但不晚于资助期结束后一年。我们正在使用RO1机制提交这项提案。

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.