Despite the public health significance of smoking, and evidence from adult twin studies for a strong genetic influence on smoking behavior (heritability estimates as high as 70%), there has been little research designed specifically to identify genes that contribute to risk of addiction to nicotine in humans. We propose a large-scale gene mapping study to identify specific chromosomal locations or candidate genes that have at least a moderate effect on risk. Families will be ascertained through panels of adult Australian and Finnish twins, and a sample of spouses of Australian twins, who have been identified as having a history of heavy smoking in earlier surveys. We will conduct diagnostic telephone interviews and blood drawing on probands, their full siblings and parents, to identify sibships with at least one affected sib pair (ASP) concordant for heavy smoking, and at least one living parent (target N=400 Australian, 400 Finnish families with approximately 600 ASPs from each). A 10cM genome-wide scan will be conducted using these families, with affected sib pair methods of linkage analysis used to identify candidate chromosomal regions suggestive of linkage. A transmission disequilibrium test approach will be used to test for candidate gene effects on nicotine dependence (DSM-IV nicotine dependence criteria and a-Fagerstrom Test for Nicotine Dependence score >= 4), and for fine mapping of candidate regions. Our study will have the advantage of having not only candidate alleles from trios (two parents plus nicotine dependent offspring), but also sibships with both nicotine dependent and non-regular (""""""""unaffected"""""""") smokers. The availability of these within family controls will increase the robustness of our inferences. Candidate genes to be tested include CYP2A6, CYP2D6, and the dopamine D1 and D2 receptor genes. A database(without personal identifiers) will be established in St. Louis that includes genotype, diagnostic, and other pertinent information, a lymphoblast cell line repository will be established in St. Louis for cell lines obtained from Australian families; and a repository in Helsinki for DNA obtained from Finnish families, for distribution to qualified members of the scientific community.
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