0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Editorial   |    
Nicotine Addiction
Wade Berrettini, M.D., Ph.D.
Am J Psychiatry 2008;165:1089-1092. doi:10.1176/appi.ajp.2008.08050780
An erratum to this article has been published | view the erratum

Given the high rates of nicotine addiction among individuals with psychiatric disorders (1, 2), readers of the Journal may be interested to know that the substantial genetic risk (3) for nicotine addiction is being elucidated, as exemplified by an article in this issue by Bierut et al. (4). In the past year, several studies have identified a cluster of nicotinic receptor subunit genes, located on chromosome 15q25, as conveying risk for nicotine addiction and other disorders.

Nicotine acts as an agonist at brain nicotinic receptors, for which the endogenous neurotransmitter is acetylcholine. Each nicotinic receptor consists of five subunits, which form a central cation (Ca++, K+, Na+) channel. The great heterogeneity of nicotinic receptors derives mostly from the multiple subunits (each with its own gene), including α2– α10 and β2– β4, which combine promiscuously to yield a wide array of brain nicotinic receptors. The specific composition of the five subunits in the receptor conveys important pharmacological characteristics of the receptor and its cation channel (5).

The complex history of recent genetic reports on these receptors and smoking begins with a genome-wide association study of about 1,000 individuals with nicotine addiction and about 900 comparison subjects (6). The study examined DNA variation across the genome, reporting limited statistical evidence for association with alleles in a cluster of nicotinic receptor genes— α3 (CHRNA3), α5 (CHRNA5), and β4 (CHRNB4) on chromosome 15q25. This report was followed by several other genome-wide association studies, implicating the same alleles, with much stronger statistical significance (see Table 1). The increased risk conveyed by the risk alleles is modest, with an odds ratio of ∼1.3.

The top part of Figure 1 presents diagrammatic sketches of the three nicotinic receptor subunit genes in the implicated region; the boxes indicate exons and the arrows indicate the direction of transcription. CHRNA3 is shown in yellow because it is coded in the reverse direction from CHRNA5 and CHRNB4. In the triangular diagram below the gene diagrams, the red areas indicate regions of high correlation among alleles (that is, the likelihood that alleles are found together, known as linkage disequilibrium), and white and blue colors indicate regions of less linkage disequilibrium. Some combinations of these alleles occur very frequently in the same individuals and form a haplotype. Haplotypes are combinations of several polymorphisms that are often inherited intact across generations and in populations with a common ancestry, such as European Americans. Alleles and their combination in haplotypes in this CHRNA3-CHRNA5-CHRNB4 cluster were thus identified as conveying risk for nicotine addiction.

The most common European haplotype in the region is the first one listed in the figure, which has a 38% frequency. This common haplotype increases risk for nicotine addiction, and it has the risk alleles identified in these studies. The second most common haplotype contains some but not all of the risk alleles. Next, there are two less common European haplotypes that are protective, containing none of the risk alleles (the third and fourth haplotypes, with 13% and 5.3% frequencies in Europeans). The last two haplotypes are uncommon among European-origin individuals, and contain some of the risk alleles.

Within this nicotinic receptor gene cluster, there may be more than one risk allele that alters gene function (4). The article by Bierut et al. in this issue of the Journal(4) reports that a nicotine addiction risk variant in the a5 nicotinic receptor gene produces a receptor with distinct binding constants and unique electrophysiologic properties. The effect of the variant at the level of the receptor’s neurobiological function thus provides a possible clue to which alterations in brain biology increase the risk for nicotine addiction.

To complicate matters further, two reports from large-scale genome-wide association studies (12, 13) have concluded that these same alleles increase the risk for lung cancer in people of European origin, with an odds ratio of 1.3. The increase in risk for lung cancer attributable to these sequences may be an example of how a genetic variant leads to a change in brain biology and thus to a change in behavior, in this case nicotine addiction, that ultimately causes cancer through habitual smoking. However, the lung cancer association may also be independent of the risk for nicotine addiction and may involve nicotine’s ability to inhibit apoptosis (programmed cell death; 14), promote cell proliferation (15), and protect against cytotoxic causes of cell death (16), making survival of tumor cells more probable.

Clearly, additional research is needed to identify more definitively all the functional variation in this complex region. Some of this variation will likely be detected in other ethnic groups, where variants in these genes may also occur. However, it is reasonably clear that at least one common haplotype increases risk for nicotine addiction. This information can be used to initiate research projects of potentially important public health impact, including the following:

1. Develop new nicotine addiction medications that “normalize” nicotinic receptor function, differences attributable to the nicotine addiction risk alleles, versus the “protective” alleles. Presumably such medications would be more efficacious in persons with the nicotine addiction risk alleles at this locus.

2. Test existing nicotine addiction pharmacotherapies to determine whether the nicotine addiction risk alleles predict response to bupropion, varenicline, or nicotine replacement therapies.

3. Create new prevention programs designed for adolescents possessing the nicotine addiction risk alleles, a laudable goal that would require genotyping a large target population and prospective assessments over years. This opportunity may be especially relevant given evidence that these alleles may preferentially predispose individuals to early onset of smoking (9, 17).

1.Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA: Nicotine dependence and psychiatric disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2004; 61:1107–1115
 
2.Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH: Smoking and mental illness: a population-based prevalence study. JAMA 2000; 284:2606–2610
 
3.Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE: Genetics of nicotine dependence and pharmacotherapy. Biochem Pharmacol 2008; 75:178–195
 
4.Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, Horton WJ, Breslau N, Budde J, Cloninger CR, Dick DM, Foroud T, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Kuperman S, Madden PAF, Mayo K, Nurnberger J Jr, Pomerleau O, Porjesz B, Reyes O, Schuckit M, Swan G, Tischfield JA, Edenberg HJ, Rice JP, Goate AM: Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 2008; 165:1163–1171
 
5.Gotti C, Moretti M, Gaimarri A, Zanardi A, Clementi F, Zoli M: Heterogeneity and complexity of native brain nicotinic receptors. Biochem Pharmacol 2007; 74:1102–1111
 
6.Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF, Swan GE, Rutter J, Bertelsen S, Fox L, Fugman D, Goate AM, Hinrichs AL, Konvicka K, Martin NG, Montgomery GW, Saccone NL, Saccone SF, Wang JC, Chase GA, Rice JP, Ballinger DG: Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16:24–35
 
7.Berrettini WH, Yuan X, Tozzi F, Song K, Chilcoat H, Francks C, Waterworth D, Muglia P, Mooser V: Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 2008; 13:368–373
 
8.Thorgeirsson TE, Geller F, Sulem P, et al: A variant associated with nicotine dependence, lung cancer, and peripheral arterial disease. Nature 452: 638-42, 2008
 
9.Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, Matsunami N, Singh NA, Baird L, Coon H, McMahon WM, Piper ME, Fiore MC, Scholand MB, Connett JE, Kanner RE, Gahring LC, Rogers SW, Hoidal JR, Leppert MF: A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet 2008; 4(7):e1000125
 
10.Chen X, Chen J, Williamson VS, An SS, Hettema JM, Aggen SH, Neale NC, Kendler K: Variants in nicotinic acetylcholine receptors a5 and a3 increase risks to nicotine but not alcohol or cannabis dependence. Biol Psychiatry (in press)
 
11.Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O, Swan GE, Goate AM, Rutter J, Bertelsen S, Fox L, Fugman D, Martin NG, Montgomery GW, Wang JC, Ballinger DG, Rice JP, Bierut LJ: Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 2007; 16:36–49
 
12.Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS: Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008; 40:616–622
 
13.Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, et al: A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008; 452:633–637
 
14.Lam DC, Girard L, Ramirez R, Chau WS, Suen WS, Sheridan S, Tin VP, Chung LP, Wong MP, Shay JW, Gazdar AF, Lam WK, Minna JD: Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res 2007; 67:4638–4647
 
15.Dasgupta P, Chellappan SP: Nicotine-mediated cell proliferation and angiogenesis: new twists to an old story. Cell Cycle 2006; 5:2324–2328
 
16.Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S: Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci USA 2006; 103:6332–6337
 
17.Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Hopfer CJ, Lessem JM, McQueen MB, Rhee SH, Ehringer MA: The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 2008; 63:1039–1046
 

+Address correspondence and reprint requests to Dr. Berrettini, Department of Psychiatry, University of Pennsylvania, Translational Research Laboratories, Rm. 2206, 125 S. 31st St., Philadelphia, PA 19104; wadeb@mail.med.upenn.edu (e-mail). Editorial accepted for publication May 2008 (doi: 10.1176/appi.ajp.2008.08050780).

+The author reports no competing interests.

 
Figure 1. Cluster of Genes Implicated in Nicotine Addiction Riska

aAnalysis of haplotype blocks in the region of CHRNA3 revealed a single large haplotype block (indicated by the largest black triangle), encompassing the CHRNA3 and CHRNA5 genes. Note that all the risk alleles are located on the first (most common in European-origin people) haplotype. The third and fourth haplotypes are protective, containing none of the risk alleles. Hence, somewhere in this ∼60,000 base-pair region are one or more functional alleles for increasing risk for nicotine dependence. They will be found only by functional studies.

Figure 1. Cluster of Genes Implicated in Nicotine Addiction Riska

aAnalysis of haplotype blocks in the region of CHRNA3 revealed a single large haplotype block (indicated by the largest black triangle), encompassing the CHRNA3 and CHRNA5 genes. Note that all the risk alleles are located on the first (most common in European-origin people) haplotype. The third and fourth haplotypes are protective, containing none of the risk alleles. Hence, somewhere in this ∼60,000 base-pair region are one or more functional alleles for increasing risk for nicotine dependence. They will be found only by functional studies.

+

References

1.Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA: Nicotine dependence and psychiatric disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2004; 61:1107–1115
 
2.Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH: Smoking and mental illness: a population-based prevalence study. JAMA 2000; 284:2606–2610
 
3.Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE: Genetics of nicotine dependence and pharmacotherapy. Biochem Pharmacol 2008; 75:178–195
 
4.Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L, Horton WJ, Breslau N, Budde J, Cloninger CR, Dick DM, Foroud T, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Kuperman S, Madden PAF, Mayo K, Nurnberger J Jr, Pomerleau O, Porjesz B, Reyes O, Schuckit M, Swan G, Tischfield JA, Edenberg HJ, Rice JP, Goate AM: Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 2008; 165:1163–1171
 
5.Gotti C, Moretti M, Gaimarri A, Zanardi A, Clementi F, Zoli M: Heterogeneity and complexity of native brain nicotinic receptors. Biochem Pharmacol 2007; 74:1102–1111
 
6.Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF, Swan GE, Rutter J, Bertelsen S, Fox L, Fugman D, Goate AM, Hinrichs AL, Konvicka K, Martin NG, Montgomery GW, Saccone NL, Saccone SF, Wang JC, Chase GA, Rice JP, Ballinger DG: Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16:24–35
 
7.Berrettini WH, Yuan X, Tozzi F, Song K, Chilcoat H, Francks C, Waterworth D, Muglia P, Mooser V: Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 2008; 13:368–373
 
8.Thorgeirsson TE, Geller F, Sulem P, et al: A variant associated with nicotine dependence, lung cancer, and peripheral arterial disease. Nature 452: 638-42, 2008
 
9.Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, Matsunami N, Singh NA, Baird L, Coon H, McMahon WM, Piper ME, Fiore MC, Scholand MB, Connett JE, Kanner RE, Gahring LC, Rogers SW, Hoidal JR, Leppert MF: A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet 2008; 4(7):e1000125
 
10.Chen X, Chen J, Williamson VS, An SS, Hettema JM, Aggen SH, Neale NC, Kendler K: Variants in nicotinic acetylcholine receptors a5 and a3 increase risks to nicotine but not alcohol or cannabis dependence. Biol Psychiatry (in press)
 
11.Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O, Swan GE, Goate AM, Rutter J, Bertelsen S, Fox L, Fugman D, Martin NG, Montgomery GW, Wang JC, Ballinger DG, Rice JP, Bierut LJ: Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 2007; 16:36–49
 
12.Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS: Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008; 40:616–622
 
13.Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, et al: A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008; 452:633–637
 
14.Lam DC, Girard L, Ramirez R, Chau WS, Suen WS, Sheridan S, Tin VP, Chung LP, Wong MP, Shay JW, Gazdar AF, Lam WK, Minna JD: Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res 2007; 67:4638–4647
 
15.Dasgupta P, Chellappan SP: Nicotine-mediated cell proliferation and angiogenesis: new twists to an old story. Cell Cycle 2006; 5:2324–2328
 
16.Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S: Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci USA 2006; 103:6332–6337
 
17.Schlaepfer IR, Hoft NR, Collins AC, Corley RP, Hewitt JK, Hopfer CJ, Lessem JM, McQueen MB, Rhee SH, Ehringer MA: The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biol Psychiatry 2008; 63:1039–1046
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 6

Related Content
Books
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 2.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 2.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 2.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 2.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 3.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles