MOLECULAR GENETICS OF HEROIN DEPENDENCE

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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.