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Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses

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Abstract

Tobacco smoking is a severe health hazard worldwide, as nearly one-third of the global adult population smokes tobacco products. This high prevalence highlights the importance of studying the genetic determinants of nicotine dependence (ND). To identify such genetic factors, more than 20 genome-wide linkage studies have been conducted across different populations using a variety of ND assessment approaches, including smoking quantity (SQ), Heaviness of Smoking Index (HSI), Fagerström Test for Nicotine Dependence (FTND), ever-smoking, habitual smoking, or maximum number of cigarettes smoked in a 24-h period. This review provides a critical update on the progress during the years since our last review, published in 2004, in identifying susceptibility loci for ND. Although a significant number of reported genomic regions did not reach the level of “suggestive” or “significant” linkage and failed to be replicated in other independent studies, thirteen regions, located on chromosomes 3–7, 9–11, 17, 20, and 22, have been found to be suggestive or significant in at least two independent samples. Among them, the regions on chromosomes 9 (91.9–136.5 cM), 10, 11, and 17 have received the strongest support. A summary of eight regions that have been nominated for “significant” linkage to ND is provided.

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References

  • Bergen AW, Korczak JF, Weissbecker KA, Goldstein AM (1999) A genome-wide search for loci contributing to smoking and alcoholism. Genet Epidemiol 17(Suppl 1):S55–S60

    PubMed  Google Scholar 

  • Bergen AW, Yang XR, Bai Y, Beerman MB, Goldstein AM, Goldin LR (2003) Genomic regions linked to alcohol consumption in the Framingham Heart Study. BMC Genet 4(Suppl 1):S101

    Article  PubMed  Google Scholar 

  • Beuten J, Ma JZ, Payne TJ, Dupont RT, Crews KM, Somes G, Williams NJ, Elston RC, Li MD (2005) Single- and multilocus allelic variants within the GABAB receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence. Am J Hum Genet 76:859–864

    Article  PubMed  CAS  Google Scholar 

  • Beuten J, Ma JZ, Lou XY, Payne TJ, Li MD (2007a) Association analysis of the protein phosphatase 1 regulatory subunit 1B (PPP1R1B) gene with nicotine dependence in European- and African-American smokers. Am J Med Genet B Neuropsychiatr Genet 144:285–290

    PubMed  Google Scholar 

  • Beuten J, Ma JZ, Payne TJ, Dupont RT, Lou XY, Crews KM, Elston RC, Li MD (2007b) 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 

  • 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  PubMed  Google Scholar 

  • Bradaia A, Berton F, Ferrari S, Luscher C (2005) Beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids. Proc Natl Acad Sci USA 102:3034–3039

    Article  PubMed  CAS  Google Scholar 

  • Carmelli D, Swan GE, Robinette D, Fabsitz R (1992) Genetic influence on smoking—a study of male twins. N Engl J Med 327:829–833

    Article  PubMed  CAS  Google Scholar 

  • CDC (2005) Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997–2001. Morb Mortal Wkly Rep 54:625–628

    Google Scholar 

  • CDC (2007) Cigarette smoking among adults—United States, 2006. Morb Mortal Wkly Rep 56:1157–1161

    Google Scholar 

  • Cen B, Yu Q, Guo J, Wu Y, Ling K, Cheng Z, Ma L, Pei G (2001) Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor. J Neurochem 76:1887–1894

    Article  PubMed  CAS  Google Scholar 

  • Cheng LS, Swan GE, Carmelli D (2000) A genetic analysis of smoking behavior in family members of older adult males. Addiction 95:427–435

    Article  PubMed  CAS  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 

  • Ehlers CL, Wilhelmsen KC (2006) Genomic screen for loci associated with tobacco usage in Mission Indians. BMC Med Genet 7:9

    Article  PubMed  CAS  Google Scholar 

  • Ehlers CL, Wilhelmsen KC (2007) Genomic screen for substance dependence and body mass index in southwest California Indians. Genes Brain Behav 6:184–191

    Article  PubMed  Google Scholar 

  • Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG (2004) Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci 27:107–144

    Article  PubMed  CAS  Google Scholar 

  • Gelernter J, Liu X, Hesselbrock V, Page GP, Goddard A, Zhang H (2004) Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking. Am J Med Genet 128B:94–101

    Article  PubMed  Google Scholar 

  • Gelernter J, Panhuysen C, Weiss R, Brady K, Poling J, Krauthammer M, Farrer L, Kranzler HR (2007) Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus. Biol Psychiatry 61:119–126

    Article  PubMed  CAS  Google Scholar 

  • Goode EL, Badzioch MD, Kim H, Gagnon F, Rozek LS, Edwards KL, Jarvik GP (2003) Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study. BMC Genet 4(Suppl 1):S102

    Article  PubMed  Google Scholar 

  • Heath AC, Martin NG (1993) Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence. Addict Behav 18:19–34

    Article  PubMed  CAS  Google Scholar 

  • Heath AC, Cates R, Martin NG, Meyer J, Hewitt JK, Neale MC, Eaves LJ (1993) Genetic contribution to risk of smoking initiation: comparisons across birth cohorts and across cultures. J Subst Abuse 5:221–246

    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 

  • Hughes JR (1986) Genetics of smoking: a brief review. Behav Therapy 17:335–345

    Article  Google Scholar 

  • Kendler KS, Neale MC, Sullivan P, Corey LA, Gardner CO, Prescott CA (1999) A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med 29:299–308

    Article  PubMed  CAS  Google Scholar 

  • Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247

    Article  PubMed  CAS  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, 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  PubMed  Google Scholar 

  • Li MD, Ma JZ, Cheng R, Dupont RT, Williams NJ, Crews KM, Payne TJ, Elston RC (2003b) A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet 4(Suppl 1):S103

    Article  PubMed  Google Scholar 

  • Li MD, Payne TJ, Ma JZ, Lou XY, Zhang D, Dupont RT, Crews KM, Somes G, Williams NJ, Elston RC (2006) A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans. Am J Hum Genet 79:745–751

    Article  PubMed  CAS  Google Scholar 

  • Li MD, Ma JZ, Payne TJ, Lou XY, Zhang D, Dupont RT, Elston RC (2007a) Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample. Mol Psychiatry 2007 June 19 [Epub ahead of print]

  • Li MD, Sun D, Lou XY, Beuten J, Payne TJ, Ma JZ (2007b) 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 

  • Li XC, Karadsheh MS, Jenkins PM, Brooks JC, Drapeau JA, Shah MS, Lautner MA, Stitzel JA (2007c) Chromosomal loci that influence oral nicotine consumption in C57BL/6J × C3H/HeJ F2 intercross mice. Genes Brain Behav 6:401–410

    Article  PubMed  CAS  Google Scholar 

  • Lou XY, Ma JZ, Sun D, Payne TJ, Li MD (2007) Fine mapping of a linkage region on chromosome 17p13 reveals that GABARAP and DLG4 are associated with vulnerability to nicotine dependence in European-Americans. Hum Mol Genet 16:142–153

    Article  PubMed  CAS  Google Scholar 

  • Loukola A, Broms U, Maunu H, Widen E, Heikkila K, Siivola M, Salo A, Pergadia ML, Nyman E, Sammalisto S, Perola M, Agrawal A, Heath AC, Martin NG, Madden PA, Peltonen L, Kaprio J (2007) Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background. Pharmacogenomics J 2007 June 5 [Epub ahead of print]

  • Madden PA, Heath AC, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG (1999) The genetics of smoking persistence in men and women: a multicultural study. Behav Genet 29:423–431

    Article  PubMed  CAS  Google Scholar 

  • Maes HH, Woodard CE, Murrelle L, Meyer JM, Silberg JL, Hewitt JK, Rutter M, Simonoff E, Pickles A, Carbonneau R, Neale MC, Eaves LJ (1999) Tobacco, alcohol and drug use in eight- to sixteen-year-old twins: the Virginia Twin Study of Adolescent Behavioral Development. J Stud Alcohol 60:293–305

    PubMed  CAS  Google Scholar 

  • Morley KI, Medland SE, Ferreira MA, Lynskey MT, Montgomery GW, Heath AC, Madden PA, Martin NG (2006) A possible smoking susceptibility locus on chromosome 11p12: evidence from sex-limitation linkage analyses in a sample of Australian Twin Families. Behav Genet 36:87–99

    Article  PubMed  Google Scholar 

  • Pomerleau OF, Pomerleau CS, Chu J, Kardia SL (2007) Genome-wide linkage analysis for smoking-related regions, with replication in two ethnically diverse populations. Nicotine Tob Res 9:955–958

    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 

  • Saccone SF, Pergadia ML, Loukola A, Broms U, Montgomery GW, Wang JC, Agrawal A, Dick DM, Heath AC, Todorov AA, Maunu H, Heikkila K, Morley KI, Rice JP, Todd RD, Kaprio J, Peltonen L, Martin NG, Goate AM, Madden PA (2007) Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples. Am J Hum Genet 80:856–866

    Article  PubMed  CAS  Google Scholar 

  • SAMHSA (2001) Summary of findings from the 2000 national household survey on drug abuse, Rockville

  • 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 

  • 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  PubMed  Google Scholar 

  • Sun D, Ma JZ, Payne TJ, Li MD (2007) Beta-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers. Mol Psychiatry 2007 June 19 [Epub ahead of print]

  • Swan GE, Carmelli D, Reed T, Harshfield GA, Fabsitz RR, Eslinger PJ (1990a) Heritability of cognitive performance in aging twins. The National Heart, Lung, and Blood Institute Twin Study. Arch Neurol 47:259–262

    PubMed  CAS  Google Scholar 

  • Swan GE, Carmelli D, Rosenman RH, Fabsitz RR, Christian JC (1990b) Smoking and alcohol consumption in adult male twins: genetic heritability and shared environmental influences. J Subst Abuse 2:39–50

    Article  PubMed  CAS  Google Scholar 

  • Swan GE, Carmelli D, Cardon LR (1996) The consumption of tobacco, alcohol, and coffee in Caucasian male twins: a multivariate genetic analysis. J Subst Abuse 8:19–31

    Article  PubMed  CAS  Google Scholar 

  • Swan GE, Hops H, Wilhelmsen KC, Lessov-Schlaggar CN, Cheng LS, Hudmon KS, Amos CI, Feiler HS, Ring HZ, Andrews JA, Tildesley E, Benowitz N (2006) A genome-wide screen for nicotine dependence susceptibility loci. Am J Med Genet B Neuropsychiatr Genet 141:354–360

    PubMed  Google Scholar 

  • True WR, Xian H, Scherrer JF, Madden PA, Bucholz KK, Heath AC, Eisen SA, Lyons MJ, Goldberg J, Tsuang M (1999) Common genetic vulnerability for nicotine and alcohol dependence in men. Arch Gen Psychiatry 56:655–661

    Article  PubMed  CAS  Google Scholar 

  • Vink JM, Beem AL, Posthuma D, Neale MC, Willemsen G, Kendler KS, Slagboom PE, Boomsma DI (2004) Linkage analysis of smoking initiation and quantity in Dutch sibling pairs. Pharmacogenomics J 4:274–282

    Article  PubMed  CAS  Google Scholar 

  • Vink JM, Willemsen G, Boomsma DI (2005) Heritability of smoking initiation and nicotine dependence. Behav Genet 35:397–406

    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 

  • 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  CAS  Google Scholar 

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

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Acknowledgments

The author thanks Drs. David Bronson, Thomas J Payne, and Jamie Mangold for their critical editing and Drs. Daolong Wang, Jennie Z. Ma, Xiang-Yang Lou, and Weihua Huang for their help in the preparation of the tables and figures used for the report. The preparation of this article was in part supported by NIH grants DA-12844 and DA-13783.

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  1. Department of Psychiatry and Neurobehavioral Sciences, Section of Neurobiology, University of Virginia, 1670 Discovery Drive, Suite 110, Charlottesville, VA, 22911, USA

    Ming D. Li

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Correspondence to Ming D. Li.

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Li, M.D. Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses. Hum Genet 123, 119–131 (2008). https://doi.org/10.1007/s00439-008-0473-0

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