VTSF_KK

Virginia Institute for Psychiatric and Behavioral Genetics

Virginia Youth Tobacco Project: Candidate Genes for Nicotine Dependence in Humans

Grant number
VTSF
8520012

Principal Investigator:
Kenneth S. Kendler

Co-investigators:
Sam Chen
Edwin van den Oord

Years:
2001-2005

Abstract

The aim of the study is to identify and characterize the individual genes that determine vulnerability to nicotine dependence (ND) in humans. Genes which influence complex traits like ND are difficult to identify. In 1999, our group published the first systematic linkage study of ND in humans. No major gene effect was found, although a few suggestive areas were delineated. Newer methods, based on association studies of candidate genes, will be needed to determine definitively the genetic basis of ND in man. Our research group has DNA samples on over 5,000 individual Virginia twins who are well characterized for their lifetime history of smoking and ND and a replicate sample of nearly 1,000 well studied young adults from New Zealand with similar data. We have a fully equipped high through-put molecular genetics laboratory and substantial experience in the statistical analysis of such data. We propose to obtain further candidate genes for ND from a detailed review of the human and animal literature regarding the biological systems that subserve nicotine metabolism and brain action, such as several nicotine receptors, dopamine receptors and metabolic enzymes. We will be working closely with Dr. Billy Martin and his colleagues in their parallel project one goal of which will be to identify using both traditional breeding methods and highly parallel gene expression arrays genes involved in the action of nicotine and in ND in rodent models. This work will capitalize on their extensive experience in animal models of nicotine action and dependence. Given the high levels of homology known to exist between the mouse and human genomes, we expect to be able to identify human homologues for nearly all the candidate genes identified by Dr. Martin and colleagues. Our task would then be to identify the relevant functional variants in those genes in human populations and to see whether those variants are associated with ND in our large population samples. If positive results are obtained, we will both be able to replicate these results in our New Zealand sample and, because of our detailed evaluation of these subjects, determine the spectrum of action of these genes. Discovery of the specific genetic variants in humans which influence liability to ND has important implications for the reduction of the disease burden imposed by tobacco use.

Keywords

Funding Agency

VTSF: Virginia Tobacco Settlement Foundation

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