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. 2009 Jul;11(7):785-96.
doi: 10.1093/ntr/ntp064. Epub 2009 May 12.

Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes

Timothy B Baker  1 , Robert B Weiss, Daniel Bolt, Andrew von Niederhausern, Michael C Fiore, Diane M Dunn, Megan E Piper, Nori Matsunami, Stevens S Smith, Hilary Coon, William M McMahon, Mary B Scholand, Nanda Singh, John R Hoidal, Su-Young Kim, Mark F Leppert, Dale S Cannon
Affiliations

Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes

Timothy B Baker et al. Nicotine Tob Res. 2009 Jul.

Abstract

Introduction: Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerström Test for Nicotine Dependence among individuals reporting daily smoking by age 17. The present study used subsamples of participants from that study to investigate associations between the CHRNA5-A3-B4 haplotypes and an array of phenotypes not analyzed previously (i.e., withdrawal severity, ability to stop smoking, and specific scales on the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) that reflect loss of control, strong craving, and heavy smoking.

Methods: Two cohorts of current or former smokers (N = 886) provided both self-report data and DNA samples. One sample (Wisconsin) comprised smokers making a quit smoking attempt, which permitted the assessment of withdrawal and relapse during the attempt. The other sample (Utah) comprised participants studied for risk factors for nicotine dependence and chronic obstructive pulmonary disease and included individuals originally recruited in the Lung Health Study.

Results: The CHRNA5-A3-B4 haplotypes were significantly associated with the targeted WISDM-68 scales (Tolerance, Craving, Loss of Control) in both samples of participants but only among individuals who began smoking early in life. The haplotypes were significantly associated with relapse likelihood and withdrawal severity, but these associations showed no evidence of an interaction with age at daily smoking.

Discussion: The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking.

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Figures

Figure 1.
Figure 1.
Linkage disequilibrium (LD) structure and haplotype frequency in the CHRNA5-A3 region using five haplotype tagging single nucleotide polymorphisms (SNPs). (A) The LD plot between pairs of SNP markers from this chromosome 15 region is based on the measured r2. Pairwise LD values (r2) are indicated at the intercept of the two SNP markers on the matrix. Each square represents the magnitude of LD for a single pair of markers, with black color indicating high r2. (B) Haplotypes spanning this LD block are shown along with their frequency in the combined Utah and Wisconsin cohorts. Chromosome 15 coordinates are from NCBI Build 36.1 (hg18).
Figure 2.
Figure 2.
Dichotomous phenotypes by haplotype (top) and diplotype (bottom). PDM, Primary Dependence Motives; Early, daily smoking at age 16 or younger; Late, daily smoking at age 17 or older; and WDR, withdrawal. High Dependence = percentage in the dichotomous category indicative of a higher level of nicotine dependence, that is, percentage above the median for PDM and WDR and the percentage who relapsed for 90-day relapse.
Figure 3.
Figure 3.
Dichotomous Primary Dependence Motives scales by haplotype (top) and diplotype (bottom) in early-onset smokers. The scales were scored dichotomously based on the median for both age-at-onset conditions.
Figure 4.
Figure 4.
Abstinence following a smoking cessation trial by haplotype (top, n = 767) and diplotype (bottom, n = 356). Abstinence is shown as the Kaplan–Meier probability of remaining abstinent for the first 90 days postquit. Data are based on the age-at-onset conditions combined.
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References

    1. Adriani W, Spijker S, Deroche-Gamonet V, Laviola G, Le Moal M, Smit AB, et al. Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats. Journal of Neuroscience. 2003;23:4712–4716. - PMC - PubMed
    1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
    1. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genetics. 2008;40:616–622. - PMC - PubMed
    1. Baker TB, Moffit T, Caspi A, Conti D. The nicotine dependence phenotype: Translating theoretical perspectives and extant data into recommendations for genetic mapping. In: Swan GE, editor. The nicotine dependence phenotype, NCI Monograph No. 22. Washington, DC: U.S. Government Printing Office; (in press)
    1. Baker TB, Piper ME, McCarthy DE, Bolt DM, Smith SS, Kim S. -Y., et al. Time to first cigarette in the morning as an index of ability to quit smoking: Implications for nicotine dependence. Nicotine & Tobacco Research. 2007;9(Suppl. 4):s555–s570. - PMC - PubMed

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