Skip to main content
SpringerLink
Log in

Significant association of DRD1 with nicotine dependence

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Epidemiologic studies have strongly implicated genetics in smoking behavior. Genes in the dopaminergic system, which mediates the reinforcing and dependence-producing properties of nicotine, are plausible candidates for roles in nicotine dependence (ND). In this study, we examined five single-nucleotide polymorphisms (SNPs) within or near the dopamine D1 receptor gene (DRD1) for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). The samples were obtained from 2,037 participants representing 200 European American (EA) and 402 African American (AA) families. Although we found significant associations of SNPs rs265973, rs686, and rs4532 in the AA sample; of rs4532 in the EA sample; and of rs265975, rs686, and rs4532 in the pooled sample with various ND measures, only the association of rs686 in the AA sample and of rs686 and rs4532 in the pooled sample remained significant after correction for multiple testing. Haplotype-based association analysis revealed that haplotype C-T-A, formed by rs265973, rs265975, and rs686, was significantly associated with all three ND measures in both the AA and the pooled sample. Another haplotype, T-A-T, formed by rs265975, rs686, and rs4532, showed a significant association with FTND in the pooled sample. Furthermore, in a luciferase reporter assay, rs686, located in the 3′ untranslated region, caused differential luciferase activities, indicating that rs686 is a functional polymorphism affecting expression of DRD1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  • Benowitz NL, Perez-Stable EJ, Fong I, Modin G, Herrera B, Jacob P 3rd (1999) Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 291:1196–1203

    PubMed  CAS  Google Scholar 

  • Beuten J, Payne TJ, Ma JZ, Li MD (2006) Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations. Neuropsychopharmacology 31:675–684

    Article  PubMed  CAS  Google Scholar 

  • Beuten J, Ma JZ, Payne TJ, Dupont RT, Lou XY, Crews KM, Elston RC, Li MD (2007) Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans. Biol Psychiatry 61:48–55

    Article  PubMed  CAS  Google Scholar 

  • Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK, Clasen LS, Sharp WS, Inoff-Germain G, Wavrant-De Vrieze F, Arcos-Burgos M, Straub RE, Hardy JA, Castellanos FX, Rapoport JL (2005) Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet 134:67–72

    PubMed  Google Scholar 

  • Cichon S, Nothen MM, Erdmann J, Propping P (1994) Detection of four polymorphic sites in the human dopamine D1 receptor gene (DRD1). Hum Mol Genet 3:209

    Article  PubMed  CAS  Google Scholar 

  • Cichon S, Nothen MM, Stober G, Schroers R, Albus M, Maier W, Rietschel M, Korner J, Weigelt B, Franzek E, Wildenauer D, Fimmers R, Propping P (1996) Systematic screening for mutations in the 5′-regulatory region of the human dopamine D1 receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder. Am J Med Genet 67:424–428

    Article  PubMed  CAS  Google Scholar 

  • Comings DE, Gade R, Wu S, Chiu C, Dietz G, Muhleman D, Saucier G, Ferry L, Rosenthal RJ, Lesieur HR, Rugle LJ, MacMurray P (1997) Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Mol Psychiatry 2:44–56

    Article  PubMed  CAS  Google Scholar 

  • Del Zompo M, De Luca V, Severino G, Ni X, Mulas S, Congiu D, Piccardi MP, Kennedy JL (2007) Haplotype association study between DRD1 gene and bipolar type I affective disorder in two samples from Canada and Sardinia. Am J Med Genet B Neuropsychiatr Genet 144:237–241

    PubMed  Google Scholar 

  • Duggirala R, Almasy L, Blangero J (1999) Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q. Genet Epidemiol 17(Suppl 1):S139–S144

    PubMed  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  PubMed  CAS  Google Scholar 

  • Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The Fagerstrom Test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 86:1119–1127

    Article  PubMed  CAS  Google Scholar 

  • Ho MK, Tyndale RF (2007) Overview of the pharmacogenomics of cigarette smoking. Pharmacogenomics J 7:81–98

    Article  PubMed  CAS  Google Scholar 

  • Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM (2004) Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26:61–69

    Article  PubMed  Google Scholar 

  • Kim DJ, Park BL, Yoon S, Lee HK, Joe KH, Cheon YH, Gwon DH, Cho SN, Lee HW, NamGung S, Shin HD (2007) 5′ UTR polymorphism of dopamine receptor D1 (DRD1) associated with severity and temperament of alcoholism. Biochem Biophys Res Commun 357:1135–1141

    Article  PubMed  CAS  Google Scholar 

  • Komarova AV, Brocard M, Kean KM (2006) The case for mRNA 5′ and 3′ end cross talk during translation in a eukaryotic cell. Prog Nucleic Acid Res Mol Biol 81:331–367

    Article  PubMed  CAS  Google Scholar 

  • Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2004) PBAT: tools for family-based association studies. Am J Hum Genet 74:367–369

    Article  PubMed  Google Scholar 

  • Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20

    Article  PubMed  CAS  Google Scholar 

  • Li MD (2006) The genetics of nicotine dependence. Curr Psychiatry Rep 8:158–164

    Article  PubMed  CAS  Google Scholar 

  • Li MD, Cheng R, Ma JZ, Swan GE (2003) A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98:23–31

    Article  PubMed  Google Scholar 

  • Li MD, Ma JZ, Beuten J (2004) Progress in searching for susceptibility loci and genes for smoking-related behaviour. Clin Genet 66:382–392

    Article  PubMed  CAS  Google Scholar 

  • Li MD, Beuten J, Ma JZ, Payne TJ, Lou XY, Garcia V, Duenes AS, Crews KM, Elston RC (2005) Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 14:1211–1219

    Article  PubMed  CAS  Google Scholar 

  • Li MD, Sun D, Lou XY, Beuten J, Payne TJ, Ma JZ (2007) Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence. Mol Psychiatry 12:462–473

    Article  PubMed  CAS  Google Scholar 

  • Limosin F, Loze JY, Rouillon F, Ades J, Gorwood P (2003) Association between dopamine receptor D1 gene DdeI polymorphism and sensation seeking in alcohol-dependent men. Alcohol Clin Exp Res 27:1226–1228

    Article  PubMed  CAS  Google Scholar 

  • Lin S, Chakravarti A, Cutler DJ (2004) Exhaustive allelic transmission disequilibrium tests as a new approach to genome-wide association studies. Nat Genet 36:1181–1188

    Article  PubMed  CAS  Google Scholar 

  • Misener VL, Luca P, Azeke O, Crosbie J, Waldman I, Tannock R, Roberts W, Malone M, Schachar R, Ickowicz A, Kennedy JL, Barr CL (2004) Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder. Mol Psychiatry 9:500–509

    Article  PubMed  CAS  Google Scholar 

  • Nisell M, Nomikos GG, Svensson TH (1994) Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16:36–44

    Article  PubMed  CAS  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769

    Article  PubMed  CAS  Google Scholar 

  • O’Connell JR, Weeks DE (1999) An optimal algorithm for automatic genotype elimination. Am J Hum Genet 65:1733–1740

    Article  PubMed  CAS  Google Scholar 

  • Perez-Stable EJ, Herrera B, Jacob P 3rd, Benowitz NL (1998) Nicotine metabolism and intake in black and white smokers. JAMA 280:152–156

    Article  PubMed  CAS  Google Scholar 

  • Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257

    Article  PubMed  CAS  Google Scholar 

  • Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, Wu JC, Alva G, Carreon DT, Bunney WE Jr, Fallon JH, Kennedy JL (2003) D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Mol Psychiatry 8:109–113

    Article  PubMed  CAS  Google Scholar 

  • Saccone NL, Neuman RJ, Saccone SF, Rice JP (2003) Genetic analysis of maximum cigarette-use phenotypes. BMC Genet 4(Suppl 1):S105

    Article  PubMed  Google Scholar 

  • Sander T, Harms H, Podschus J, Finckh U, Nickel B, Rolfs A, Rommelspacher H, Schmidt LG (1995) Dopamine D1, D2 and D3 receptor genes in alcohol dependence. Psychiatr Genet 5:171–176

    Article  PubMed  CAS  Google Scholar 

  • Severino G, Congiu D, Serreli C, De Lisa R, Chillotti C, Del Zompo M, Piccardi MP (2005) A48G polymorphism in the D1 receptor genes associated with bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet 134:37–38

    PubMed  Google Scholar 

  • Sullivan PF, Kendler KS (1999) The genetic epidemiology of smoking. Nicotine Tob Res 1(Suppl 2):S51–S57 (discussion S69–S70)

    Article  PubMed  Google Scholar 

  • Vink JM, Posthuma D, Neale MC, Eline Slagboom P, Boomsma DI (2006) Genome-wide linkage scan to identify loci for age at first cigarette in Dutch sibling pairs. Behav Genet 36:100–111

    Article  PubMed  Google Scholar 

  • Wall JD, Pritchard JK (2003) Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 4:587–597

    Article  PubMed  CAS  Google Scholar 

  • Wong AH, Buckle CE, Van Tol HH (2000) Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 410:183–203

    Article  PubMed  CAS  Google Scholar 

  • World Health Organization Tobacco Free Initiative (2005) Waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators. World Health Organization, Geneva

Download references

Acknowledgments

We are grateful for the invaluable contributions of clinical information and blood by all participants in the genetic study, as well as the dedicated work of many research staff at different clinical sites. We are also very thankful for the excellent editing made by Dr. David L. Bronson on this paper. This project was funded by National Institutes of Health grants DA-12844 and DA-13783 (to M.D.L.).

Author information

Authors and Affiliations

  1. Department of Psychiatry and Neurobehavioral Sciences, Section of Neurobiology, University of Virginia, 1670 Discovery Drive, Suite 125, Charlottesville, VA, 22911, USA

    Weihua Huang, Joke Beuten & Ming D. Li

  2. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    Jennie Z. Ma

  3. ACT Center for Tobacco Treatment, Education and Research, University of Mississippi Medical Center, Jackson, MS, USA

    Thomas J. Payne

  4. Department of Criminology and Criminal Justice, University of Memphis, Memphis, TN, USA

    Randolph T. Dupont

Authors
  1. Weihua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennie Z. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas J. Payne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joke Beuten
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Randolph T. Dupont
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming D. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming D. Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, W., Ma, J.Z., Payne, T.J. et al. Significant association of DRD1 with nicotine dependence. Hum Genet 123, 133–140 (2008). https://doi.org/10.1007/s00439-007-0453-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-007-0453-9

Keywords

Search

Navigation