Genetic Variation in Dopamine Pathways Differentially Associated With Smoking Progression in Adolescence

doi:10.1097/CHI.0b013e31816bff77

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 47, Issue 6, June 2008, Pages 673-681

https://doi.org/10.1097/CHI.0b013e31816bff77 Get rights and content

ABSTRACT

Objective:

To clarify the nature of the association between dopamine genes and smoking by examining whether genetic variability in components of the dopamine pathway could explain refined phenotypes in adolescent smoking progression.

Method:

Data are from an ongoing prospective study of the long-term outcome of early risk factors studied since birth. At age 15 years, 220 participants (108 males, 112 females) completed a self-report questionnaire measuring smoking behavior and were genotyped for five dopamine gene variants.

Results:

Smoking initiation was related to allelic variation in the dopamine D4 receptor gene (DRD4), whereas smoking continuation and dependence showed association with the dopamine D2 receptor gene (DRD2). Adolescents with the seven-repeat allele of the common DRD4 exon 3 polymorphism had rates of ever smoking that were significantly higher than in those with other genotypes. Once smoking started, carriers of the T allele of a single nucleotide polymorphism of DRD2 (rs4648317) reported higher rates of current smoking and scored higher on nicotine dependence than their allelic counterparts. Among current smokers, intention to quit was significantly lower in adolescents homozygous for the 10-repeat allele of the common dopamine transporter 3′ untranslated region polymorphism.

Conclusions:

Our results provide preliminary evidence of genetic influences on different stages of smoking and suggest the importance of specific dopamine genes in smoking progression in adolescence.

Section snippets

Participants.

Participants were selected from the Mannheim Study of Children at Risk, a large-scale, prospective, longitudinal study of the outcome of early risk factors from infancy into adolescence.³⁴ The initial sample comprised 384 children of predominantly (>99.0%) European descent born between 1986 and 1988. Infants were recruited from two obstetric and six children's hospitals of the Rhine-Neckar region of Germany and were included consecutively into the sample according to a two-factor design

RESULTS

Table 2 presents measures of tobacco consumption for male and female adolescents in the sample. The findings of linear and logistic regression analyses testing the simultaneous effects of dopamine genotypes on different smoking phenotypes are summarized in Table 3. Analyses revealed an association of smoking initiation with DRD4. Carriers of the 7r allele, compared to those without this allele, exhibited significantly higher rates of lifetime smoking (70.0% > 53.8%, odds ratio [OR] 1.97,

DISCUSSION

The present study sought to extend our understanding of the association between dopamine genes and cigarette smoking by examining whether genetic variability in components of the dopamine pathway was differentially related to refined phenotypes in adolescent smoking. Our results confirmed previous inconsistent findings mostly from adult smokers demonstrating significant relationships between several dopamine genotypes and smoking behavior. In particular, our results provided evidence that

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This association, however, did not remain significant after corrections for multiple comparisons, but these results within the context of Ducci et al. (2011) and Audrain-McGovern et al. (2004), point to the involvement of DRD2 variants in heavy smoking and/or nicotine dependence. Another dopamine receptor isoform gene, DRD4 (Dopamine Receptor D4) has been investigated as a candidate gene for smoking behaviors in adults, with mixed results (Das et al., 2011; Laucht et al., 2008; Shields et al., 1998). Results in adolescents for an association of DRD4 have also been mixed.
Nicotine use continues to be a major public health concern, with an alarming recent rise in electronic cigarette consumption. Heritability estimates of nicotine use and abuse range from 40% to 80%, providing strong evidence that genetic factors impact nicotine addiction-relevant phenotypes. Although nicotine use during adolescence is a key factor in the development of addiction, it remains unclear how genetic factors impact adolescent nicotine use and abuse. This review will discuss studies investigating genetic factors impacting nicotine use during adolescence. Evidence from both rodent and human studies will be summarized and integrated when possible. Human adolescent studies have largely included candidate gene studies for genes identified in adult populations, such as genes involved in nicotine metabolism, nicotinic acetylcholine receptor signaling, dopaminergic signaling, and other neurotransmitter signaling systems. Alternatively, rodent studies have largely taken a discovery-based approach identifying strain differences in adolescent nicotine addiction-relevant behaviors. Here, we aim to answer the following three questions by integrating human and rodent findings: (1) Are there genetic variants that uniquely impact nicotine use during adolescence? (2) Are there genetic variants that impact both adolescent and adult nicotine use? and (3) Do genetic factors in adolescence significantly impact long-term consequences of adolescent nicotine use? Determining answers for these three questions will be critical for the development of preventative measures and treatments for adolescent nicotine use and addiction.
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Dopamine D4 receptor (DRD4) dysregulation is associated with a variety of behaviors including novelty-seeking, approach avoidance, and ADHD. DRD4 has also been shown to interact with the environment to produce changes in behavior and longevity. The present study sought to examine the role of DRD4 on cocaine-seeking behavior in the conditioned place preference (CPP) test and determine its effects on extinction and reinstatement in adult wild-type (WT), heterozygous (HT), and knockout (KO) mice. Results revealed that all mice, regardless of sex or genotype, developed a similar acquisition for a cocaine place preference. Female DRD4 KO mice failed to extinguish their preference for the cocaine-paired chamber following the extinction period. Male DRD4 KO mice failed to reinstate their preference after a priming dose following successful extinction. No differences in locomotor activity were observed within drug treatment conditions due to genotype, and female mice displayed reduced locomotor activity during CPP conditioning compared to male mice. The observed effects illustrate the role DRD4 gene expression has on extinction and reinstatement, but not acquisition, of cocaine-seeking behavior.
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NCAM1-TTC12-ANKK1-DRD2 variants became a focus of smoking molecular genetics due to the critical role of dopamine D2 receptors (DRD2) in nicotine pharmacodynamics (Benowitz, 2010). This chromosome 11q23 gene cluster has been associated with ND in studies using both genome-wide and candidate approaches (Bergen et al., 2009; Ducci et al., 2011; Laucht et al., 2008; Morley et al., 2006; Saccone et al., 2007), including a handful in AAs (David et al., 2010; Gelernter et al., 2006; Huang et al., 2009). Although meta-analyses support a role for DRD2 in smoking risk (Li et al., 2004; Munafò et al., 2004), heterogeneity of effects exists across studies and meta-analytic reports call for additional studies using non-EA participants.
Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences that may vary across ethnicities. The use of intermediate phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work in European Americans has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives represent core features of nicotine dependence and are promising intermediate phenotypes for understanding genetic pathways to ND. However, no studies have examined PDM as an intermediate phenotype in African American smokers, an ethnic population that displays unique patterns of smoking and genetic variation. In the current study, 268 African American daily smokers completed a phenotypic assessment and provided a sample of DNA. Associations among haplotypes in the NCAM1-TTC12-ANKK1-DRD2 gene cluster, a dopamine-related gene region associated with ND, PDM intermediate phenotypes, and ND were examined. Dopamine-related genetic variation in the DBH and COMT genes was also considered on an exploratory basis. Mediational analysis was used to test the indirect pathway from genetic variation to smoking motives to nicotine dependence. NCAM1-TTC12-ANKK1-DRD2 region variation was significantly associated with the Automaticity subscale and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and ND. DBH was also significantly associated with Automaticity, Craving, and Tolerance; Automaticity and Tolerance also served as mediators of the DBH–ND relationship. These results suggest that PDM, Automaticity in particular, may be a viable intermediate phenotype for understanding dopamine-related genetic influences on ND in African American smokers. Findings support a model in which putatively dopaminergic variants exert influence on ND through an effect on patterns of automatic routinized smoking.
COMT met allele differentially predicts risk versus severity of aberrant eating in a large community sample
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Therefore, the effect of COMT genotype on risk for body dissatisfaction may not become evident unless other risk factors such as depressed mood are present, which may explain the lack of an association between COMT genotype and risk of body dissatisfaction in the present study. Candidate gene studies in other clinical populations have also demonstrated that there may be unique genetic influences on risk, severity, progression, and clinical presentation of a given phenotype (Goghari and Sponheim, 2008; Laucht et al., 2008; Parsa et al., 2013). For instance, variation in the gene encoding apolipoprotein 1 was found to predict progression of, but not risk for, chronic kidney disease (Parsa et al., 2013).
Prefrontal dopamine (DA) transmission participates in the reinforcement of reward-driven behaviors like eating. Because catechol-O-methyltransferase (COMT) degrades DA and is expressed in the prefrontal cortex, variation in the COMT gene may modulate eating behavior. Previous studies have shown that the met allele of the COMT val158met single nucleotide polymorphism (SNP) is associated with Bulimia Nervosa (BN). The specific aim of this study was to test whether the met allele increased risk for, and severity of, eating disorder symptomatology in community volunteers. Caucasian adults (N=1003; 51.2% female) from the University of Pittsburgh Adult Health and Behavior Project (AHAB) were genotyped and completed the Eating Disorders Inventory (EDI). Logistic and Poisson regression analyses assessed genotype-dependent presence and severity of eating disorder symptomatology. The met allele was significantly associated with the presence of symptoms on the Bulimia subscale and the severity of Body Dissatisfaction scores. All EDI subscales significantly predicted BMI. To our knowledge, these are the first data indicating that the COMT met allele increases risk for some symptoms of disordered eating, while increasing severity of others, in a community sample. These novel findings may have important implications for understanding the etiology of heterogeneous disordered eating phenotypes.
Genetics and pain
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Nonetheless, allele testing, genotyping, and haplotyping did show nominally significant P values for some SNPs or genes, particularly SNPs from DRD2 in chromosome 11 (rs12364283 and rs4648317), which presented the lowest P values. Both have been associated with enhanced DRD2 expression and linked to several addictive behaviors, such as nicotine dependence (rs4648317),33 inhibition and impulsivity related to response to d-amphetamine on stop-task performance, and mood ratings (rs12364283).34 They are but 2 of many SNPs linked to dopamine pathway dysregulation, which has also been observed in patients with chronic pain unrelated to substance addiction.35
It has been well known for years that there is considerable interindividual variability in the sensitivity to and tolerance of experimental pain stimuli, in the propensity to develop painful pathologies, and in the response to analgesic therapies; however, this does not mean that such differences are because of genetic factors alone, as pain is a complex phonemenon in which psychological and environmental factors, for example, as well as those inherent to physiological mechanisms, play an important role. Several different methods are used in genetic pain research. Although the identification of mutations can explain some very infrequent pathologies that follow Mendelian patterns of inheritance, the research method used in most cases is the genetic association study, which tests the correlation between a certain phenoytpe (pain) and a polymorphism or single-nucleotide polymorphism. At present there is evidence suggesting that genetic factors may be at least partially responsible for the greater pain experienced by certain individuals following an acute injury, such as a surgical intervention; however, studies analyzing the influence of genetics on chronic postsurgical pain have been scarce.

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This study was supported by grants from the Deutsche Forschungsgemeinschaft, from the Federal Ministry for Education and Research (grant 01EB0110), "Baden-Wuerttemberg Consortium for Addiction Research," the National Genome Research Network (grant 01GS0117), and from the Foundation of the Landesbank Baden-Württemberg, Germany.

The authors thank the parents and children for their participation in the study.

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NEW RESEARCHGenetic Variation in Dopamine Pathways Differentially Associated With Smoking Progression in Adolescence

ABSTRACT

Objective:

Method:

Results:

Conclusions:

Section snippets

Participants.

RESULTS

DISCUSSION

Chest.

Med Hypotheses.

Neuropharmacology.

Eur J Pharmacol.

Prog Neuropsychopharmacol Biol Psychiatry.

J Am Acad Child Adolesc Psychiatry.

Biol Psychiatry.

Neuropsychopharmacology.

Addict Behav.

J Am Acad Child Adolesc Psychiatry.

Neuronal nicotinic receptors: from structure to function

Nicotine Tob Res.

The genetic basis for smoking behavior: a systematic review and meta-analysis

Nicotine Tob Res.

The genetics of nicotine dependence

Curr Psychiatry Rep.

Conditioning of opioid reinforcement: neuroanatomical and neurochemical substrates

Ann N Y Acad Sci.

From neurobiology to treatment: progress against addiction

Nat Neurosci.

D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele

Pharmacogenetics.

Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1

Hum Mutat.

Evaluation of a structural polymorphism in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene and the activation of executive attention networks

Cogn Affect Behav Neurosci.

Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex

Am J Psychiatry.

The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking

Pharmacogenetics.

The dopamine D2 receptor (DRD2) gene-a genetic risk factor in heavy smoking?

Addict Biol.

Lack of association between the dopamine D2 receptor gene allele DRD2*A1 and cigarette smoking in a United Kingdom population

Pharmacogenetics.

Progress in searching for susceptibility loci and genes for smoking-related behaviour

Clin Genet.

NEW RESEARCH
Genetic Variation in Dopamine Pathways Differentially Associated With Smoking Progression in Adolescence

Lack of association between the dopamine D2 receptor gene allele DRD2A1* and cigarette smoking in a United Kingdom population