Skip to main content

Advertisement

SpringerLink
Log in

Gene-based analysis suggests association of the nicotinic acetylcholine receptor β1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence

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

Abstract

Based on our previously identified linkage regions for nicotine dependence (ND), we selected six and five single nucleotide polymorphisms (SNPs) in the muscarinic cholinergic receptor subtype M1 (CHRM1) and nicotinic cholinergic receptor β1 (CHRNB1), respectively, to determine the association of the two genes with ND in a total of 2,037 subjects from 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP- and/or haplotype-based analyses indicated that the CHRNB1 was significantly associated with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND), in both ethnic samples. The association of rs2302763 in the CHRNB1 was significant with adjusted SQ in the EA sample after correction for multiple testing (P = 0.013). Haplotype A-T-A formed by SNPs rs2302765, rs2302762, and rs9217 in the CHRNB1 was significantly associated with the high risk allele for all the three ND measures (minimum P = 0.009, 0.006, and 0.008 for SQ, HSI and FTND, respectively) in the AA sample while haplotype A-T-A formed by rs2302765, rs2302763, and rs9217 was significantly positively associated with ND (minimum P = 0.005, 0.016, and 0.016 for SQ, HSI and FTND, respectively) in the EA sample. The CHRM1 exhibited significant protective associations of haplotype C-C-A-T-G-G formed by all six SNPs of this gene with at least one ND measure in the AA sample after Bonferroni correction (minimum P = 0.008, 0.013, and 0.009 for SQ, HSI and FTND, respectively), but no significant association was found in the EA sample. The significant associations, together with their location of linked region to ND, suggest that the CHRNB1 and CHRM1 are likely candidates for further investigation.

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

Similar content being viewed by others

References

  • Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M (2004) Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 75:998–1014

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Berrettini WH, Lerman CE (2005) Pharmacotherapy and pharmacogenetics of nicotine dependence. Am J Psychiatry 162:1441–1451

    Article  PubMed  Google Scholar 

  • Bierut LJ, Rice JP, Goate A, Hinrichs AL, Saccone NL, Foroud T, Edenberg HJ, Cloninger CR, Begleiter H, Conneally PM, Crowe RR, Hesselbrock V, Li TK, Nurnberger JI Jr, Porjesz B, Schuckit MA, Reich T (2004) A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence. Am J Med Genet 124A:19–27

    Article  Google Scholar 

  • Clark AG (2004) The role of haplotypes in candidate gene studies. Genet Epidemiol 27:321–333

    Article  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 

  • Felder CC, Porter AC, Skillman TL, Zhang L, Bymaster FP, Nathanson NM, Hamilton SE, Gomeza J, Wess J, McKinzie DL (2001) Elucidating the role of muscarinic receptors in psychosis. Life Sci 68:2605–2613

    Article  PubMed  CAS  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 

  • Gotti C, Clementi F (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–396

    Article  PubMed  CAS  Google Scholar 

  • Hamilton SE, Hardouin SN, Anagnostaras SG, Murphy GG, Richmond KN, Silva AJ, Feigl EO, Nathanson NM (2001) Alteration of cardiovascular and neuronal function in M1 knockout mice. Life Sci 68:2489–2493

    Article  PubMed  CAS  Google Scholar 

  • Hamilton SE, Schlador ML, McKinnon LA, Chmelar RS, Nathanson NM (1998) Molecular mechanisms for the regulation of the expression and function of muscarinic acetylcholine receptors. J Physiol Paris 92:275–278

    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 

  • Henningfield JE, Fant RV (1999) Tobacco use as drug addiction: the scientific foundation. Nicotine Tob Res 1(Suppl 2):S31–S35

    Article  PubMed  Google Scholar 

  • Henningfield JE, Jude NR (1999) Prevention of nicotine addiction: neuropsychopharmacological issues. Nicotine Tob Res 1(Suppl 1):S41–S48

    Article  PubMed  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 

  • http://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor Muscarinic acetylcholine receptor. From Wikipedia, the free encyclopedia

  • Hu D, Cao K, Peterson-Wakeman R, Wang R (2002) Altered profile of gene expression in rat hearts induced by chronic nicotine consumption. Biochem Biophys Res Commun 297:729–736

    Article  PubMed  CAS  Google Scholar 

  • Karlin A (2002) Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3:102–114

    Article  PubMed  CAS  Google Scholar 

  • Lange C, Silverman EK, Xu X, Weiss ST, Laird NM (2003) A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 4:195–206

    Article  PubMed  Google Scholar 

  • Le Novere N, Corringer PJ, Changeux JP (2002) The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53:447–456

    Article  PubMed  CAS  Google Scholar 

  • Levey AI (1993) Immunological localization of m1–m5 muscarinic acetylcholine receptors in peripheral tissues and brain. Life Sci 52:441–448

    Article  PubMed  CAS  Google Scholar 

  • Levey AI (1996) Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci USA 93:13541–13546

    Article  PubMed  CAS  Google Scholar 

  • Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95:221–227

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

    Article  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, Ma JZ, Cheng R, Dupont R, Williams KC, Payne TJ, Elston RC (2003b) A genome wide scan to identify loci for smoking quantity in the Framingham Heart Study populations. BMC Genet 4(Suppl 1):S103

    Article  Google Scholar 

  • Lukas RJ, Ke L, Bencherif M, Eisenhour CM (1996) Regulation by nicotine of its own receptors. Drug Dev Res 38:136–148

    Article  CAS  Google Scholar 

  • Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of death in the United States, 2000. JAMA 291:1238–1245

    Article  PubMed  Google Scholar 

  • Munafo MR, Shields AE, Berrettini WH, Patterson F, Lerman C (2005) Pharmacogenetics and nicotine addiction treatment. Pharmacogenomics 6:211–223

    Article  PubMed  CAS  Google Scholar 

  • Neale BM, Sham PC (2004) The future of association studies: gene-based analysis and replication. Am J Hum Genet 75:353–362

    Article  PubMed  CAS  Google Scholar 

  • Niu T, Chen C, Ni J, Wang B, Fang Z, Shao H, Xu X (2000) Nicotine dependence and its familial aggregation in Chinese. Int J Epidemiol 29:248–252

    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 (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Caldarone BJ, King SL, Zachariou V (2000) Nicotinic receptors in the brain. Links between molecular biology and behavior. Neuropsychopharmacology 22:451–465

    Article  PubMed  CAS  Google Scholar 

  • Rose JE (1996) Nicotine addiction and treatment. Annu Rev Med 47:493–507

    Article  PubMed  CAS  Google Scholar 

  • Stallings MC, Corley RP, Dennehey B, Hewitt JK, Krauter KS, Lessem JM, Mikulich-Gilbertson SK, Rhee SH, Smolen A, Young SE, Crowley TJ (2005) A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence. Arch Gen Psychiatry 62:1042–1051

    Article  PubMed  CAS  Google Scholar 

  • Straub RE, Sullivan PF, Ma Y, Myakishev MV, Harris-Kerr C, Wormley B, Kadambi B, Sadek H, Silverman MA, Webb BT, Neale MC, Bulik CM, Joyce PR, Kendler KS (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 4:129–144

    Article  PubMed  CAS  Google Scholar 

  • Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG, Hogenesch JB (2002) Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 99:4465–4470

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Sullivan PF, Neale BM, van den Oord E, Miles MF, Neale MC, Bulik CM, Joyce PR, Straub RE, Kendler KS (2004) Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. Am J Med Genet B Neuropsychiatr Genet 126:23–36

    Article  Google Scholar 

  • Sullivan PF, Neale MC, Silverman MA, Harris-Kerr C, Myakishev MV, Wormley B, Webb BT, Ma Y, Kendler KS, Straub RE (2001) An association study of DRD5 with smoking initiation and progression to nicotine dependence. Am J Med Genet 105:259–265

    Article  PubMed  CAS  Google Scholar 

  • Swan GE (1999) Implications of genetic epidemiology for the prevention of tobacco use. Nicotine Tob Res 1(Suppl 1):S49–S56

    Article  PubMed  Google Scholar 

  • USDHHS (1988) The health consequences of smoking: nicotine addiction. A report of the surgeon general. Department of Health and Human Services, Washington, DC

  • USDHHS (2000) Reducing tobacco use: a report of the surgeon general. US Department of Health & Human Services, Center for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promortion, Atlanta, GA

  • Wang D, Ma JZ, Li MD (2005) Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis. Pharmacogenomics J 5:166–172

    Article  PubMed  Google Scholar 

  • Watkins SS, Koob GF, Markou A (2000) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res 2:19–37

    Article  PubMed  CAS  Google Scholar 

  • WHO (2002) The World Health Report 2002. World Health Organization

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatric Medicine, University of Virginia, 1670 Discovery Drive, Suite 101, Charlottesville, VA, 22911, USA

    Xiang-Yang Lou, Jennie Z. Ma, Joke Beuten & Ming D. Li

  2. The ACT Center for Tobacco Treatment, Education and Research, University of Mississippi Medical Center, 2500, North State Street, Jackson, MS, 39216-4505, USA

    Thomas J. Payne & Karen M. Crew

Authors
  1. Xiang-Yang Lou
    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. Karen M. Crew
    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

Lou, XY., Ma, J.Z., Payne, T.J. et al. Gene-based analysis suggests association of the nicotinic acetylcholine receptor β1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. Hum Genet 120, 381–389 (2006). https://doi.org/10.1007/s00439-006-0229-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0229-7

Keywords

Search

Navigation