This project seeks to identify regions of the human genome that contain genetic loci that influence the susceptibility to cigarette smoking (CS) and nicotine dependence (ND). In 1967, the US Surgeon General's report concluded that """"""""smoking is the prototypical substance-abuse dependency."""""""" The US contains 45 million nicotine- dependent smokers and tobacco use is responsible for over 400,000 deaths annually. Twin and adoption studies in man have conclusively shown that genetic factors substantially influence the risk for CS and ND, and these results are confirmed by studies in rodents. Specifically, we propose to study three epidemiologic samples for which we are already funded to collect DNA and information on lifetime smoking habits. We request support to select from these samples 400 dizygotic twin or non-twin sibling pairs particularly infomative for CS/ND. We will select pairs in which either both members are high nicotine- dependent regular smokers or one member is so classified and his sibling experimented with cigarettes but never developed a regular smoking habit. On the first 200 of these pairs, we will complete a genome wide scan using 400 highly polymorphic markers. Positive findings will then be replicated in the next 200 pairs. We will also study additional sibling pairs to clarify the genetic basis of low nicotine-dependent regular smoking. A variety of statistical methods, including multipoint mapping and multivariate genetic analyses, will be used to detect and localize individual susceptibility genes for CS/ND in the selected samples. Further analyses will permit us to clarify the spectrum of action of these loci, determining whether they also impact on personality and/or the risk for psychiatric illness or other forms of drug abuse/dependence. Once chromosomal regions containing susceptibility genes for CS/ND have been identified, the tools of molecular biology can, in subsequent work, be applied to identify the specific genes and understand their mode of action. This will provide major insights into the brain mechanisms involved in susceptibility to CS and ND.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010228-03
Application #
2458462
Study Section
Special Emphasis Panel (SRCD (56))
Project Start
1995-09-30
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Neale, Benjamin M; Sullivan, Patrick F; Kendler, Kenneth S (2005) A genome scan of neuroticism in nicotine dependent smokers. Am J Med Genet B Neuropsychiatr Genet 132B:65-9
Sullivan, Patrick F; Neale, Benjamin M; van den Oord, Edwin et al. (2004) Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. Am J Med Genet B Neuropsychiatr Genet 126B:23-36
Sullivan, P F; Jiang, Y; Neale, M C et al. (2001) Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence. Am J Med Genet 105:479-84
Kendler, K S; Thornton, L M; Pedersen, N L (2000) Tobacco consumption in Swedish twins reared apart and reared together. Arch Gen Psychiatry 57:886-92
Silverman, M A; Neale, M C; Sullivan, P F et al. (2000) Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence. Am J Med Genet 96:646-53
Straub, R E; Sullivan, P F; Ma, Y et al. (1999) Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol Psychiatry 4:129-44
Sullivan, P F; Kendler, K S (1999) The genetic epidemiology of smoking. Nicotine Tob Res 1 Suppl 2:S51-7;discussion S69-70