2006 - 2007 Publications > Genetics on Nicotine Addiction

Genetics on nicotine addiction

Brown et al (2007) analyzed the effect of the alpha 5 nicotinic receptor knockout on the distribution and function of nicotinic receptors.  Although 20 percent of nicotinic receptors in the mouse brain are oligomeric complexes, deletion of the alpha 5 nicotinic receptor resulted in no change in the total number of nicotinic receptor but altered epibatidine evoked transmitter release.  These results suggest that the behavioral changes in alpha5 knockout mice are produced by alterations in the loss of function of high affinity activation site conferred by the alpha 5 subunit. J Neurochem. 2007 Oct;103(1):204-15.

Marks et al (2007) reports that nicotinic receptor containing alpha4beta2 subunits mediate high and low affinity epibatidine evoked release of 86Rb+ efflux from synaptosomes.  Neuropharmacology. 2007 Sep;53(3):390-405.

Booker et al (2007) analyzed the effect of the beta 3 nicotinic receptor knockout on measures of anxiety. Booker et al report that Beta 3 nicotinic receptor subunit knockout mice spend more time in an open field and more time in an elevated plus maze compared to wildtype littermate controls.  At the same time no effect of genotype was observed in the black/white box or in the mirror chamber.  Elevations in corticosterone were seen at baseline and in response to stress.  Booker et al suggests that nicotinic receptors containing beta3 nicotinic receptor subunit may regulate anxiety reponses to selective form of stimuli. Pharmacol Biochem Behav. 2007 May;87(1):146-57.

In a previous study Li and colleagues showed a suggestive linkage for nicotine dependence on chr 9q22-q23 in the Framingham Heart Study population.  Li et al (2007), now, report that SNPs for Shc3 that lie within the linkage region are associated with nicotine dependence in independent samples obtained from both African American and European Americans.  These variants of the Shc3 account for between 40 to 59 percent of the linkage signal detected on chromosome 9.  Mol Psychiatry. 2007 May;12(5):462-73

In a report by Huang et al (2007) SNP rs4532 in the DRD1 receptor gene is significantly associated with nicotine dependence in both Americans of African and European descent.  In a larger sample achieved by combining both samples  rs686, a SNP in the 3’ untranslated region of DRD1 receptor gene in addition to rs4532 were reported to be significantly associated with FTND, HSI (heavy smoking index), and SQ (smoking quanitities), all measures of nicotine dependence.  The luciferase gene fused with DRD1 3′ UTR with the rs686/G allele showed less expression of luciferase than when the luciferase gene was fused with DRD1 3′ UTR with the rs686/A allele.  Thus, the allelic difference in rs686 in the DRD1 3′ UTR appears to control the functional expression of DRD1. Hum Genet. 2008 Mar;123(2):133-40

Ehringer et al (2007) Am J Med Genet B Neuropsychiatr Genet.  Jul 5;144(5):596-604 and Zeiger et al (2008) Hum Mol Genet. Mar 1;17(5):724-34 suggest that the gene variants in the beta2, beta3, alpha6 subunits of the nicotinic receptor affect the initial subjective response to alcohol and nicotine.   Ehringer found a strong association between an upstream SNP (rs2072658) and negative physical response to tobacco in American of European and Hispanic descent.  An adverse reaction to alcohol was only reported in adolescents of European descent. Individuals with a rare T instead C allele in the SNP in exon 6 of CHRNB2 (rs2072660) were less likely to feel dizzy or nausea upon first use of cigarettes.   Both adverse and positive subjective responses were associated four SNPs (rs4950, rs13280604, hCV25772398 and rs4953) in the beta3 nicotinic receptor gene.

Loukola et al (2007) Pharmacogenomics J. 2007 Jun 5 conducted a linkage study of nicotine dependence and smoking behavior in 153 Finish twin families with a total of 505 individuals.  Loukola et al (2007) reports a LOD score of 3.12 on chr. 10q25 for individuals who had smoked more than 100 cigarettes in a lifetime, and was also associated with binge drinking (max two-point LOD 2.49).  These results replicate those of Straub et al (1999) Mol Psychiatry; 4: 129–144.  Suggestive linkage for nicotine dependence was also observed on chr 5q34 (LOD of 2.66), 7q21–31(LODS of1.61 to 2.5) and 11p15 (LOD 2.25).  The observation of linkage on 7q21-31 overlaps with a previous study on smoking and drinking by Madden and her colleagues.  The finding of linkage on Chr 11p15 (LOD of2.25) close to the DRD4 gene with nicotine dependence appears to corroborate the finding of the Gelernter lab. Am J Med Genet B Neuropsychiatr Genet 2004; 128: 94–101. |  

Pomerleau et al (2007) Nicotine Tob Res. 2007 Sep;9(9):955-8 reports the finding of linkage in the same region of chromosome 3 for American of European (LOD = 1.76@109 cM)  and African ancestry (LOD = 2.03@122 cM) for smoking .  The combined LOD score is 3.24@124 cM.

In an Irish sample of 626 sibling pairs ascertained for alcohol dependence, Sullivan et al (2008) Drug Alcohol Depend. 2008 Mar 1;93(3):210-6   reports the finding of suggestive linkage of combined FTND (fagerstrom score) and alcohol symptom counts based on DSM-IV on  an 11cM region on chr7 (D7S2252-D7S691, empirical p=0.0006) and  an 8cM region on chr18 flanking D18S63 (empirical p=0.0007).  These linkage results did exceed statistical significance set at p=0.0001 but is consistent with the findings of linkage for smoking in the Framingham sample by Li et al 2003 BMC Genet. 2003 Dec 31;4 Suppl 1:S103.  However, no overlapping signal was found for nicotine dependence on a region of chromosome 4 that had previously been shown to be associated with alcohol dependence symptom counts.  This suggests that the signal on chr. 4 is unique to alcoholism.

David et al (2007) Nicotine Tob Res. 2007 Aug;9(8):821-33 report that smokers with the A2/A2 DRD2-Taq genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion at 6 months in a double blind study and placebo-controlled trial.  Further individuals with the A2/A2 DRD2-Taq genotype that also possessed the CYP2B6 1459 T/T or C/T genotype showed even higher rates of abstinence. A larger sample size is needed to confirm these findings.

Salas et al (2007) Neuropharmacology. 2007 Dec;53(7):863-9  reports decreased withdrawal symptoms but normal tolerance to nicotine in mice null for the alpha7 nicotinic acetylcholine receptor subunit.

In a genome-wide expression profiling study, Philibert et al (2007) used lymphoblast cell lines from 6 actively smoking Iowa Adoption Studies (IAS) subjects and 9 "clean" control subjects, followed by real-time PCR (RT-PCR) of gene expression patterns in lymphoblast derived RNA from 94 subjects in the IAS. The expression levels of 579 of 29,098 genes were significantly up-regulated and expression levels of 584 of 29,098 genes were significantly down-regulated in lymphoblast lines from currently smoking subjects. RT-PCR confirmation of four select RNA levels confirmed the validity of the overall profile and revealed highly significant relationships between the expression of some of these transcripts and (1) major depression, (2) antisocial personality, (3) nicotine dependence, and (4) cannabis dependence. Am J Med Genet B Neuropsychiatr Genet. 2007 Jul 5;144(5):683-90

Bierut et al, 2007 screened 2.4 million SNPs in nicotine dependent cases and compared them to non-dependent smokers.  35 SNPs were among the top signals, and they nominated several novel genes in nicotine dependence (cell adhesion genes, signal transduction genes, and transcription factor genes.  A known gene was also in the second tier of signals (b3 nicotinic cholinergic receptor). Hum Mol Genet.2007  Jan 1 16(1);24-35.

Saccone et al, 2007 screened 3,713 SNPs from over 300 candidate genes in conjunction with the Bierut whole-genome scan.  39 SNPs were among the top signals, and they represented many of the cholinergic nicotinic receptor genes.  CHRNB3 showed the strongest signal and this was also a top signal in the genome-wide analysis.  Other hits were CHRNA5, KCNJ6, and GABRA4. Hum Mol Genet 2007 Jan 1 16(1): 36-49.

Swan et al, 2006 report a peak LOD score of 2.7 for Fagerstrom Test for Nicotine Dependence at 178 cM on chromosome 6 with peak closest to D6S446; a LOD scores of 2.9 for quantity of cigarettes smoked per day at 62 cM on chr 5, near D6S446; a LOD score of  3.0 for DSM-IV like severity at 164 cM on chr 7 at  D7S636; a LOD of DSM-IV dependence at 31 cM on chr 8 near D8S258;  a LOD of 4.0 for ever quiting smoking for more than one month but less than a year at cM 70 on chr 16 near D16S415; and a LOD of 2.9 for  smoking one or more cigarettes on most days at cM 90 on chr 19, D18S572. Am J Med Genet B Neuropsychiatr Genet. 2006 Jun 5;141(4):354-60

Zhang et al  et al, 2006 report that a three marker haplotype (rs9479757-rs2075572-rs10485057) for the mu opioid receptor (OPRM1) is significantly associated with smoking initiation but only nominally associated with nicotine dependence Behav Brain Funct. 2006 Aug 4;2:28

Zhang et al 2006 report that smoking initiation is associated with a major haplotype, 1-1-2-2-1 for rs1234221-rs2299939-rs1234213-rs2735343-rs70184, of PTEN (phosphatase and tensin homolog gene) is associated with smoking initiation while a minor haplotype of PTEN (about 3%), 1-2-2-2-1 for the same five SNPs, is observed only in the high nicotine dependence group.  This gene maps to the same region the chromosome 10q23 linkage peak found in a previous genome wide scan. Am J Med Genet B Neuropsychiatr Genet. 2006 Jan 5;141(1):10-4

McCallum et al, 2006 reports that deletion of the beta 2 nicotinic acetylcholine receptor subunit alters development of tolerance to nicotine and eliminates receptor upregulation   Psychopharmacology (Berl). 2006 Mar;184(3-4):314-27

Gelernter et al, 2006 previously reported a modest linkage peak (lod score of 1.97) for nicotine dependence for DSM-IV nicotine dependence in at 11q23, a region that includes a NCAM1-TTC12-ANKK1-DRD2 gene cluster.  Gelernter now reports that a haplotype spanning TTC12 and ANKK1 is strongly associated with nicotine dependence in both African American and European American populations.  Because of linkage disequilibrium these results may contribute to earlier results documenting association at the DRD2 locus with substance dependence.  Hum Mol Genet. 2006 Dec 15;15(24):3498-507

Gelernter et al 2007 conducted a genome wide linkage scan for DSM-IV ND and FTND score from a sample obtained for opioid and cocaine dependence.  Gelernter et al 2007 reports a maximum lod score of 3.04 on chromosome 5 at 95.40 cM (marker D5S248) for the FTND trait in the AA part of the sample.  But most interestingly, Gelernter obtained a nominal linkage on chromosome 9 at 95–100 cM,for FTND in European Americans that maps to same region previously found in other linkage studies in overlapping samples by Gelenter and by Li, and Bierut.  Biol Psychiatry. 2007 Jan 1; 61(1), 119-126 

Yu et al, 2006 reports that an intronic variant and haplotypes in the dopa decarboxylase gene on chr 7 are associated with FTND and DSM-IV in European-American and African Americans. These results confirm the results of Ma et al 2005 and localize the site of the gene variant. Hum Mol Genet. 2006 Jul 15;15(14):2192-9

Ray et al 2006 reports that the A118G variant of OPRM1 is associated with the reinforcing properties of nicotine in women but not in men, suggesting a significant gender interaction with OPRM1.   Psychopharmacology (Berl). 2006 Oct;188(3):355-63

Berrettini et al, 2007 reports that COMT haplotypes at rs737865 and rs165599 may predict a favorable outcome for bupropion treatment for smoking cessation. European-American smokers with a G allele at both SNPs may not benefit from bupropion treatment.  Biol. Psychiatry 2007 Jan 1;61(1), 111-118

Beuten et al 2006 report gender and ethnic specific haplotypes of catechol-O-methyltransferase (COMT) associated with nicotine dependence. Regardless of gender and ethnicity haplotypes, the high enzyme activity Val allele is always present in the protective haplotypes while the low enzyme activity Met allele is always present in high risks alleles for nicotine dependence.  Neuropsychopharmacology. 2006 Mar;31(3):675-84

Dahl et al 2006 report a significant interaction between between the DRD2 receptor promoter variant (DRD2-141) and the calcium sensor-1 (FREQ), a gene that regulates D2 receptor desensitization, genotypes on abstinence at the end of nicotine replacement therapy; 62% of the smokers with at least one copy of the DRD2 -141 Del allele and two copies of the FREQ rs1054879 A allele were abstinent from smoking, compared to 29-38% abstinence rates for other smokers in the trial.   Pharmacogenomics J. 2006 May-Jun;6(3):194-9

Lerman et al 2006 provides a preliminary report that suggests bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 - 141 Ins C allele, while Nicotine Replacement Therapy (NRT) may be more beneficial for those who carry the Del C allele of DRD2.  A larger study is needed to confirm these results Neuropsychopharmacology. 2006 Jan;31(1):231-42

Li et al 2006 found significant linkage (LOD 4.17) on chromosome 10q22, near marker D10S143 at 92cM  and suggestive linkage on chromosome 9q31 at marker D9S1825 ,  chromosome 11p11 between markers D11S1993 and D11S1344 , and chromosome 13q13 between markers D13S325 and D13S788, for major genetic determinants of ND as measured by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND) in an African American  sample. Am J Hum Genet. 2006 Oct;79(4):745-51

Previously, Li and his colleague identified linkage peaks on chr 11 and chr 17 for nicotine dependence from a sample analyzed in the Framingham Heart Study.  Lou et al 2006 tested whether the muscarinic cholinergic receptor subtype M1 (CHRM1) and nicotinic cholinergic receptor beta1 (CHRNB1) that maps to the peaks on chr 11 and chr 17, respectively are associated with nicotine dependence in the sample collected by Li of 2037 subjects.  SNP and haplotype analysis by Lou et al 2006 suggests that CHRNB1 is significantly associated with nicotine dependence as measured by smoking quantity (SQ), the Heaviness of Smoking Index (HIS) and Fagerstrom Test for nicotine dependence (FTND) in both African American and European American samples.  In contract, Lou et al reports an association for nicotine dependence for CHRM1 with nicotine dependence in African Americans Hum Genet. 2006 Oct;120(3):381-9
 
The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) maps to a region on chromosome 9q22-q23 that showed a "suggestive" linkage to nicotine dependence (ND) in a previous linkage study by Li and his colleagues.  Beuten et al 2007 reports that the haplotype T-T-A of rs1659400-rs1187272-rs1122530 had a highly significant positive association, with nicotine dependence in the European American sample and a major haplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4075274-rs729560, showed a significant positive association with nicotine dependence in the African American sample.  Biol Psychiatry. 2007 Jan 1; 61(1), 48-55

Castane et al 2006 report that the rewarding effects of nicotine are decreased in Adenosine A2A knockout mice.  This study suggests that Adenosine A2A receptor plays an important role in modulating nicotine reward.  Neuropharmacology. 2006 Sep;51(3):631-40

Morley et al identified suggestive linkage on chromosome 11p12 and a 6p12 for quantity of cigarettes consumed Behav Genet. 2006 Jan;36(1):87-99.  The finding of linkage on chr. 11p12 replicates the finding of Li et al (2003) (11p11) and Goode et al (2003) for cigarettes consumed and maps to the same region as found by Bierut et al (2004) for habitual smoking co-morbid with alcoholism  in the COGA sample.  The results for 6p12 replicate the results of two previous studies Vink et al (2004) and Duggirala et al. (1999)

Staley et al 2006 Looked at human tobacco smokers in early abstinence have higher levels of beta2 containing nicotinic acetylcholine receptors than non-smokers J Neurosci. 2006 Aug 23;26(34):8707-14

Feng et al 2006 demonstrated that worms (c. elegans) lacking TRPC (transient receptor potential canonical) channels do not respond to acutely to nicotine or show withdrawal or sensitization to nicotine.  The behaviors could be rescued by a human TRPC channel.  Feng et al also showed the PLCbeta is required for responses to nicotine.  These results suggest that release of intracellular calcium and the activation of PLCbeta is necessary for nicotine-dependent behavior.  Cell. 2006 Nov 3;127(3):621-33

Li et al report the identification of chromosomal loci on mouse Chr 1 at 96 cM (peak LOD score = 15.7)., chr 4 at 52 cM (peak LOD score = 4.1),, chr 7 (peak LOD score = 6.1) at 15cM, and chr 15 at 56 cM (peak LOD score = 4.8) that influence the amount of nicotine consumed per day.  Chromosomal loci on Chr 1, Chr 4, and Chr 15 were associated with increased consumption while chr 7 appeared to be protective. The 4 loci account for 62% of the variance of nicotine consumed.  Chr 1 that accounts for most of the variance for nicotine consumed maps to syntenic regions of chr1 that have previously been reported to be associated with nicotine consumption in humans (Wang et al, 2005; Bergen and Caporaso, 1999; Goode et al 2003).  Genes Brain Behav. 2006 Sep 8; [Epub ahead of print]