Tobacco is one of the most widely abused substances, killing more than 438,000 US citizens each year. Economically, smoking is responsible for about 7% of total US health care costs, or an estimated $167 billion each year. Genetic and epidemiological studies demonstrate that nicotine dependence (ND) is a complex disorder determined by genetic and environmental factors. Our previous meta-analysis of reported twin studies indicated that the weighted mean heritability for ND is 56% in adult smokers. To identify susceptibility loci for ND, we performed four genome-wide linkage studies on three independent samples, in which the African American (AA) and European American (EA) samples of the Mid-South Tobacco Family (MSTF) cohort were recruited by us during the first funding period of this grant. Our linkage analyses revealed four regions on chromosomes 9 (two regions), 11, and 18, in both the AA and EA samples of the MSTF cohort. In addition, we identified five regions on chromosomes 2, 4, 10, 12, and 17, which are specific for the EA sample, and two more regions, on chromosomes 10 and 13, that are unique to the AA sample. Considering that 1) we first reported "significant" linkage on chromosome 10 and "suggestive" linkage on chromosomes 9, 11, and 13 for ND in the AA population and 2) we have the largest collection of samples from this ethnic group in the US, in the current application, we seek support to follow up and expand our ongoing efforts in searching susceptibility genes for ND. Specifically, our aims are: 1) To perform high density association study on our AA family sample to screen for both common and rare risk variants for ND;2) To have sufficient power to detect the small effect of susceptibility loci for ND, we plan to continue our recruitment effort, with the final goal of collecting 2,000 unrelated individuals with ND and 2,000 unrelated control individuals who have tried tobacco smoking but did not develop ND symptoms;and 3) To replicate nominal significantly associated single nucleotide polymorphisms (SNPs) identified in the AA family sample from Aim 1 using 2,000 AA cases and 2,000 AA controls recruited from Aim 2. We expect that such a sample size will have sufficient power to detect 80% of true effects with an odds ratio (OR) as low as 1.3. We expect the completion of the proposed studies to greatly advance our understanding of the genetic determinants of ND in African American smokers that eventually will allow targeting of novel prevention and treatment strategies to individuals at risk.

Public Health Relevance

This renewal application is proposed to follow up and expand our ongoing efforts in searching susceptibility genes for nicotine dependence in African-American population. Specifically, we will perform a genome-wide association study on our AA family sample and then replicate these findings in an independent case-control sample.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012844-13
Application #
8444727
Study Section
Special Emphasis Panel (ZRG1-HOP-G (02))
Program Officer
Pollock, Jonathan D
Project Start
1999-09-30
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2013
Total Cost
$905,633
Indirect Cost
$284,189
Name
University of Virginia
Department
Psychiatry
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Yang, J; Wang, S; Yang, Z et al. (2015) The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry 20:1467-78
Li, Dawei; Zhao, Hongyu; Kranzler, Henry R et al. (2015) Genome-wide association study of copy number variations (CNVs) with opioid dependence. Neuropsychopharmacology 40:1016-26
Dash, Bhagirathi; Li, Ming D (2014) Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) ?2 subunit influence nAChR function. Neuropharmacology 85:471-81
Dash, Bhagirathi; Li, Ming D (2014) Analysis of rare variations reveals roles of amino acid residues in the N-terminal extracellular domain of nicotinic acetylcholine receptor (nAChR) alpha6 subunit in the functional expression of human alpha6*-nAChRs. Mol Brain 7:35
Dash, Bhagirathi; Li, Ming D; Lukas, Ronald J (2014) Roles for N-terminal extracellular domains of nicotinic acetylcholine receptor (nAChR) ?3 subunits in enhanced functional expression of mouse ?6?2?3- and ?6?4?3-nAChRs. J Biol Chem 289:28338-51
Yang, Jiekun; Li, Ming D (2014) Association and interaction analyses of 5-HT3 receptor and serotonin transporter genes with alcohol, cocaine, and nicotine dependence using the SAGE data. Hum Genet 133:905-18
Wang, Shaolin; Yang, Zhongli; Ma, Jennie Z et al. (2014) Introduction to deep sequencing and its application to drug addiction research with a focus on rare variants. Mol Neurobiol 49:601-14
Dash, Bhagirathi; Lukas, Ronald J; Li, Ming D (2014) A signal peptide missense mutation associated with nicotine dependence alters ?2*-nicotinic acetylcholine receptor function. Neuropharmacology 79:715-25
Wang, Shaolin; D van der Vaart, Andrew; Xu, Qing et al. (2014) Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations. Hum Genet 133:575-86
Zhu, Zhixiang; Tong, Xiaoran; Zhu, Zhihong et al. (2013) Development of GMDR-GPU for gene-gene interaction analysis and its application to WTCCC GWAS data for type 2 diabetes. PLoS One 8:e61943

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