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1.  Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data 
Nicotine & Tobacco Research  2009;11(1):64-76.
Introduction:
Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence.
Methods:
Our a priori hypothesis was that the association of the DRD2 Taq1A polymorphism with smoking behavior would be more prominent in females than males. We therefore investigated the strength of evidence for an association between the DRD2 Taq1A polymorphism and smoking behavior in a large sample of females and used meta-analytic techniques to synthesize existing published data and explore the role of sex in explaining any heterogeneity between studies.
Results:
We did not observe any strong evidence of association between the DRD2 Taq1A polymorphism and smoking behavior, including smoking initiation, smoking persistence, and smoking rate, either in our female sample or in our meta-analysis of 29 studies, comprising 28 published studies and the data from the present study. Metaregression suggested an association between the proportion of male participants in a study and the individual study effect size, indicating a larger effect size with a greater proportion of male participants for smoking initiation and smoking persistence. This effect did not appear to be due to the inclusion of the data from the present study.
Discussion:
Available evidence does not support an association between the DRD2 Taq1A polymorphism and smoking behavior. Contrary to our a priori hypothesis, we found evidence of a stronger association in males than in females.
doi:10.1093/ntr/ntn012
PMCID: PMC3203402  PMID: 19246443
2.  CHRNA3 rs1051730 Genotype and Short-Term Smoking Cessation 
Nicotine & Tobacco Research  2011;13(10):982-988.
Introduction:
The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom.
Methods:
Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis.
Results:
There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta-analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially.
Conclusions:
Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking.
doi:10.1093/ntr/ntr106
PMCID: PMC3179672  PMID: 21690317
3.  Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure 
Background
Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.
Methods
We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided.
Results
Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10−6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10−11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42).
Conclusions
Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
doi:10.1093/jnci/djs191
PMCID: PMC3352832  PMID: 22534784
4.  Association of COMT Val108/158Met Genotype and Cigarette Smoking in Pregnant Women 
Nicotine & Tobacco Research  2010;13(2):55-63.
Introduction:
Smoking behaviors, including heaviness of smoking and smoking cessation, are known to be under a degree of genetic influence. The enzyme catechol O-methyltransferase (COMT) is of relevance in studies of smoking behavior and smoking cessation due to its presence in dopaminergic brain regions. While the COMT gene is therefore one of the more promising candidate genes for smoking behavior, some inconsistencies have begun to emerge.
Methods:
We explored whether the rs4680 A (Met) allele of the COMT gene predicts increased heaviness of smoking and reduced likelihood of smoking cessation in a large population-based cohort of pregnant women. We further conducted a meta-analysis of published data from community samples investigating the association of this polymorphism with heaviness of smoking and smoking status.
Results:
In our primary sample, the A (Met) allele was associated with increased heaviness of smoking before pregnancy but not with the odds of continuing to smoke in pregnancy either in the first trimester or in the third trimester. Meta-analysis also indicated modest evidence of association of the A (Met) allele with increased heaviness of smoking but not with persistent smoking.
Conclusions:
Our data suggest a weak association between COMT genotype and heaviness of smoking, which is supported by our meta-analysis. However, it should be noted that the strength of evidence for this association was modest. Neither our primary data nor our meta-analysis support an association between COMT genotype and smoking cessation. Therefore, COMT remains a plausible candidate gene for smoking behavior phenotypes, in particular, heaviness of smoking.
doi:10.1093/ntr/ntq209
PMCID: PMC3028189  PMID: 21106664
5.  Weekly versus basic smoking cessation support in primary care: a randomised controlled trial 
Thorax  2007;62(10):898-903.
Background
There is insufficient and conflicting evidence about whether more intensive behavioural support is more effective than basic behavioural support for smoking cessation and whether primary care nurses can deliver effective behavioural support.
Methods
A randomised controlled trial was performed in 26 UK general practices. 925 smokers of ⩾10 cigarettes per day were randomly allocated to basic or weekly support. All participants were seen before quitting, telephoned around quit day, and seen 1 and 4 weeks after the initial appointment (basic support). Participants receiving weekly support had an additional telephone call at 10 days and 3 weeks after the initial appointment and an additional visit at 2 weeks to motivate adherence to nicotine replacement and renew quit attempts. 15 mg/16 h nicotine patches were given to all participants. The outcome was assessed by intention to treat analyses of the percentage confirmed sustained abstinence at 4, 12, 26 and 52 weeks after quit day.
Results
Of the 469 and 456 participants in the basic and weekly arms, the numbers (%) who quit and the percentage difference were 105 (22.4%) vs 102 (22.4%), 0.1% (95% CI −5.3% to 5.5%) at 4 weeks, 66 (14.1%) vs 52 (11.4%), −2.6% (95% CI −6.9% to 1.7%) at 12 weeks, 50 (10.7%) vs 40 (8.8%), −1.9% (95% CI −5.7% to 2.0%) at 26 weeks and 36 (7.7%) vs 30 (6.6%), −1.1% (95% CI −4.4% to 2.3%) at 52 weeks.
Conclusions
The absolute quit rates achieved are those expected from nicotine replacement alone, implying that neither basic nor weekly support were effective. Primary care smoking cessation treatment should provide pharmacotherapy with sufficient support only to ensure it is used appropriately, and those in need of support should be referred to specialists.
doi:10.1136/thx.2006.071837
PMCID: PMC2094265  PMID: 17483139
6.  5-HTTLPR Genotype and Anxiety-Related Personality Traits: A meta-analysis and new data 
We investigated the strength of evidence for association of the 5-HTTLPR polymorphism and the personality trait of Harm Avoidance. We used new primary data from a large sample of adults drawn from the Finnish population. We also applied meta-analytic techniques to synthesize existing published data. The large number studies of the 5-HTTLPR polymorphism allowed us to apply a formal test of publication bias, as well as formally investigate the impact of potential moderating factors such as measurement instrument.
Univariate ANOVA of primary data (n = 3,872), with 5-HTTLPR genotype as a between-groups factor, indicated no evidence of association with Harm Avoidance (p = 0.99). Meta-analysis indicated no evidence of significant association of 5-HTTLPR with Harm Avoidance (d = 0.02, p = 0.37), or EPQ Neuroticism (d = 0.01, p = 0.71), although there was evidence of association with NEO Neuroticism (d = 0.18, p < 0.001).
Our analyses indicate that the 5-HTTLPR variant is not associated with Harm Avoidance. Together with our previous analyses of a large sample of participants with extreme Neuroticism scores (defined by the EPQ), we have data that excludes a meaningful genetic effect of the 5-HTTLPR on two measures of anxiety-related personality traits. There remains the possibility that the variant influences the NEO personality questionnaire measure of Neuroticism. However, a large, well-powered primary study is required to test this hypothesis directly and adequately.
doi:10.1002/ajmg.b.30808
PMCID: PMC2819421  PMID: 18546120
5-HTTLPR; Genotype; Meta-Analysis; Neuroticism; Harm Avoidance
7.  The endophenotype concept in psychiatric genetics 
Psychological Medicine  2006;37(2):163-180.
The idea that some phenotypes bear a closer relationship to the biological processes that give rise to psychiatric illness than diagnostic categories has attracted considerable interest. Much effort has been devoted to finding such endophenotypes, partly because it is believed that the genetic basis of endophenotypes will be easier to analyse than that of psychiatric disease. This belief depends in part on the assumption that the effect sizes of genetic loci contributing to endophenotypes are larger than those contributing to disease susceptibility, hence increasing the chance that genetic linkage and association tests will detect them. We examine this assumption by applying meta-analytical techniques to genetic association studies of endophenotypes. We find that the genetic effect sizes of the loci examined to date are no larger than those reported for other phenotypes. A review of the genetic architecture of traits in model organisms also provides no support for the view that the effect sizes of loci contributing to phenotypes closer to the biological basis of disease is any larger than those contributing to disease itself. While endophenotype measures may afford greater reliability, it should not be assumed that they will also demonstrate simpler genetic architecture.
doi:10.1017/S0033291706008750
PMCID: PMC2829981  PMID: 16978446
8.  Credible genetic associations? 
The proliferation in genetic association studies, and the recurring failure of initially promising findings to robustly replicate, demonstrates the need for stringent standards to ensure the identification of credible associations. The Human Genome Epidemiology Network has recently published intermin guideliness on evidential criteria for genetic association studies. These are reviewed, and their value and importance discussed, as well as the impact these guidelines will have on the conduct of genetic association studies.
PMCID: PMC3076746  PMID: 21537450
Genetic association; replication; HuGENet; Meta-Analysis
9.  Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-Analysis 
Biological psychiatry  2007;63(9):852-857.
Background:
We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship.
Methods:
We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry.
Results:
Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes.
Conclusions:
Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.
doi:10.1016/j.biopsych.2007.08.016
PMCID: PMC2755289  PMID: 17949693
5-HTTLPR; amygdala; fMRI; meta-analysis; serotonin transporter gene
10.  Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers 
PLoS Genetics  2014;10(12):e1004799.
We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00×10−10), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38×10−5). An interaction test confirmed that these estimates differed from each other (P = 4.95×10−13). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.
Author Summary
We found that a single nucleotide polymorphism in the CHRNA5-A3-B4 gene cluster, which is known to influence smoking heaviness, is associated with lower body mass index (BMI) in current smokers, but higher BMI in never smokers. This difference in effects suggests that the variant influences BMI both via pathways other than smoking, and via the weight-reducing effects of smoking, in opposite directions. The overall effect on BMI would therefore be undetectable in an unstratified genome-wide association study, indicating that novel associations may be obscured by hidden population sub-structure.
doi:10.1371/journal.pgen.1004799
PMCID: PMC4256159  PMID: 25474695
11.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
Aims
To evaluate associations of treatment and an ‘additive genetic efficacy score’ (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled in two randomized clinical trials of smoking cessation therapies.
Design
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.
Setting
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
Participants
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Measurements
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Findings
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (HR = 1.29, 95%CI 1.17–1.41, p=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
Conclusions
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
doi:10.1111/add.12325
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
12.  USING MENDELIAN RANDOMISATION TO INFER CAUSALITY IN DEPRESSION AND ANXIETY RESEARCH 
Depression and Anxiety  2013;30(12):1185-1193.
Depression and anxiety co-occur with substance use and abuse at a high rate. Ascertaining whether substance use plays a causal role in depression and anxiety is difficult or impossible with conventional observational epidemiology. Mendelian randomisation uses genetic variants as a proxy for environmental exposures, such as substance use, which can address problems of reverse causation and residual confounding, providing stronger evidence about causality. Genetic variants can be used instead of directly measuring exposure levels, in order to gain an unbiased estimate of the effect of various exposures on depression and anxiety. The suitability of the genetic variant as a proxy can be ascertained by confirming that there is no relationship between variant and outcome in those who do not use the substance. At present, there are suitable instruments for tobacco use, so we use that as a case study. Proof-of-principle Mendelian randomisation studies using these variants have found evidence for a causal effect of smoking on body mass index. Two studies have investigated tobacco and depression using this method, but neither found strong evidence that smoking causes depression or anxiety; evidence is more consistent with a self-medication hypothesis. Mendelian randomisation represents a technique that can aid understanding of exposures that may or may not be causally related to depression and anxiety. As more suitable instruments emerge (including the use of allelic risk scores rather than individual single nucleotide polymorphisms), the effect of other substances can be investigated. Linkage disequilibrium, pleiotropy, and population stratification, which can distort Mendelian randomisation studies, are also discussed.
doi:10.1002/da.22150
PMCID: PMC4235433  PMID: 23847157
instrumental variable; genetics; causal inference; substance use
13.  A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation 
We conducted a cost-effectiveness analysis of genetic testing for smoking cessation, based on data available from the published pharmacogenetic studies of nicotine replacement therapy and bupropion, and a previous cost-effectiveness analysis of smoking cessation treatments. We use multiparameter evidence synthesis methods to combine evidence on cessation by genotype with evidence on cessation irrespective of genotype (which can be written as a function of genotype-specific parameters). Our intention was to explore the most cost-effective approach to prescribing smoking cessation pharmacotherapy, given the hypothetical availability of a test based on a single-gene variant that has been reported to predict treatment response. We considered four types of treatment: nicotine replacement therapy (NRT) pharmacotherapy, bupropion SR pharmacotherapy, combination NRT and bupropion, and standard care as the control. Two scenarios were investigated, one in which the control represented brief advice and the other in which the control represented individual counseling. Strategies that either do not test for dopamine D2 receptor (DRD2) genotype (each individual receives the same treatment), or do test for DRD2 genotype (treatment allocated according to genotype), were evaluated. Our results indicated that the most cost-effective strategy in our hypothetical example of a single-gene test to aid prescription of smoking cessation pharmacotherapy is to prescribe both NRT and bupropion regardless of genotype, as a first-line treatment for smoking cessation. We conclude that it should not be assumed that genetic tailoring will necessarily be more cost-effective than applying the current “one-size-fits-all” model of pharmacotherapy for smoking cessation. In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest.
doi:10.1080/14622200701767761
PMCID: PMC2257987  PMID: 18188764
14.  Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials 
We analyzed pooled data from two comparable randomized placebo-controlled clinical trials of bupropion pharmacotherapy for smoking cessation for which data on DRD2 Taq1A genotype were available. A total of 722 smokers across the two trials were randomized to 10 weeks of sustained-release bupropion hydrochloride or placebo. General estimating equation analysis demonstrated a significant gene × drug interaction (B=0.87, SE=0.34, p=.009). Smokers with the A2/A2 genotype using bupropion were more than three times as likely, relative to placebo, to be abstinent at end of treatment (35.2% vs. 15.1%; OR=3.25, 95% CI 2.00–5.28) and at 6 months of follow-up (26.7% vs. 12.2%; OR=2.81, 95% CI 1.66–4.77), which was attenuated by 12 months (16.3% vs. 10.7%; OR=1.70, 95% CI 0.95–3.05). We found no significant benefit of bupropion relative to placebo on smoking cessation outcomes at any time point in participants with A1/A1 or A1/A2 genotypes. These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype.
doi:10.1080/14622200701705027
PMCID: PMC2128730  PMID: 18058343
15.  Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation 
This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N=291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3′ VNTR), and cytochrome P450 2B6 (CYP2B6 1459 C→T) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 × bupropion interaction (B=1.49, SE=0.59, p=.012) and a three-way DRD2 × bupropion × craving interaction on 6-month smoking cessation outcomes (B=−0.45, SE=0.22, p=.038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 × CYP2B6 interaction (B=1.43, SE=0.56, p=.01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene × gene and gene × craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.
doi:10.1080/14622200701382033
PMCID: PMC2039873  PMID: 17654295
16.  Association of COMT Val108/158Met Genotype with Smoking Cessation in a Nicotine Replacement Therapy Randomized Trial 
We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype × treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies, but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy.
doi:10.1158/1055-9965.EPI-06-0936
PMCID: PMC2031911  PMID: 17548664
17.  Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium 
BMJ Open  2014;4(10):e006141.
Objectives
To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.
Design
Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress.
Participants
Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA).
Primary outcome measures
Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis.
Results
The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers.
Conclusions
Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
doi:10.1136/bmjopen-2014-006141
PMCID: PMC4187451  PMID: 25293386
Mendelian randomisation; Smoking; Depression; Anxiety
18.  Effects of varenicline and cognitive bias modification on neural response to smoking-related cues: study protocol for a randomized controlled study 
Trials  2014;15(1):391.
Background
Smoking-related cues can trigger drug-seeking behaviors, and computer-based interventions that reduce cognitive biases towards such cues may be efficacious and cost-effective cessation aids. In order to optimize such interventions, there needs to be better understanding of the mechanisms underlying the effects of cognitive bias modification (CBM). Here we present a protocol for an investigation of the neural effects of CBM and varenicline in non-quitting daily smokers.
Methods/Design
We will recruit 72 daily smokers who report smoking at least 10 manufactured cigarettes or 15 roll-ups per day and who smoke within one hour of waking. Participants will attend two sessions approximately one week apart. At the first session participants will be screened for eligibility and randomized to receive either varenicline or a placebo over a seven-day period. On the final drug-taking day (day seven) participants will attend a second session and be further randomized to one of three CBM conditions (training towards smoking cues, training away from smoking cues, or control training). Participants will then undergo a functional magnetic resonance imaging scan during which they will view smoking-related pictorial cues. Primary outcome measures are changes in cognitive bias as measured by the visual dot-probe task, and neural responses to smoking-related cues. Secondary outcome measures will be cognitive bias as measured by a transfer task (modified Stroop test of smoking-related cognitive bias) and subjective mood and cigarette craving.
Discussion
This study will add to the relatively small literature examining the effects of CBM in addictions. It will address novel questions regarding the neural effects of CBM. It will also investigate whether varenicline treatment alters neural response to smoking-related cues. These findings will inform future research that can develop behavioral treatments that target relapse prevention.
Trial registration
Registered with Current Controlled Trials: ISRCTN65690030. Registered on 30 January 2014.
doi:10.1186/1745-6215-15-391
PMCID: PMC4197256  PMID: 25294104
19.  Pathways Between Childhood Victimization and Psychosis-like Symptoms in the ALSPAC Birth Cohort 
Schizophrenia Bulletin  2012;39(5):1045-1055.
Background: Several large population-based studies have demonstrated associations between adverse childhood experiences and later development of psychotic symptoms. However, little attention has been paid to the mechanisms involved in this pathway and the few existing studies have relied on cross-sectional assessments. Methods: Prospective data on 6692 children from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) were used to address this issue. Mothers reported on children’s exposure to harsh parenting and domestic violence in early childhood, and children self-reported on bullying victimization prior to 8.5 years. Presence of children’s anxiety at 10 years and their depressive symptoms at 9 and 11 years were ascertained from mothers, and children completed assessments of self-esteem and locus of control at 8.5 years. Children were interviewed regarding psychotic symptoms at a mean age of 12.9 years. Multiple mediation analysis was performed to examine direct and indirect effects of each childhood adversity on psychotic symptoms. Results: The association between harsh parenting and psychotic symptoms was fully mediated by anxiety, depressive symptoms, external locus of control, and low self-esteem. Bullying victimization and exposure to domestic violence had their associations with psychotic symptoms partially mediated by anxiety, depression, locus of control, and self-esteem. Similar results were obtained following adjustment for a range of confounders and when analyses were conducted for boys and girls separately. Conclusions: These findings tentatively suggest that specific cognitive and affective difficulties in childhood could be targeted to minimize the likelihood of adolescents exposed to early trauma from developing psychotic symptoms.
doi:10.1093/schbul/sbs088
PMCID: PMC3756772  PMID: 22941743
etiology; bullying; longitudinal; psychosis; trauma
20.  Exploring the associations between sleep problems and chronic musculoskeletal pain in adolescents: A prospective cohort study 
Sleep problems and chronic pain are intimately connected, with pain causing poor sleep, which, in turn, leads to increased pain intensity. This may be particularly relevant among adolescents, in whom sleep patterns are more likely to be disrupted. In this study, the relationship between sleep problems at 15 years of age, and chronic regional pain as well as chronic widespread pain at 17 years of age was explored.
BACKGROUND:
The prevalence of musculoskeletal chronic pain in adolescents is estimated to be approximately 4% to 40%. The development of musculoskeletal pain during teenage years could have a marked impact on physical, psychological and social well-being.
OBJECTIVE:
To examine whether sleep problems during adolescence are associated with musculoskeletal pain, particularly chronic regional pain and chronic widespread pain.
METHODS:
Using data from the Avon Longitudinal Study of Children, the relationship between sleep problems at 15 years of age and the presence of chronic regional and widespread pain at 17 years of age was explored. Pain data were not available at 15 years of age. A total of 2493 participants with complete data were identified. Relationships among sleep problems and musculoskeletal pain were examined using logistic regression. ORs were calculated after adjusting for sex, ethnicity, socioeconomic position and depression (15 years of age).
RESULTS:
Sleep disturbance (usually wakes up more than two or three times), difficulties with hypersomnolence and poor subjective sleep perception were associated with the presence of both musculoskeletal regional and widespread pain. Finally, using ordered logistic regression, poor subjective sleep perception was also found to be associated with greater pain severity in participants with chronic musculoskeletal regional and widespread pain.
DISCUSSION:
The results of the present study suggest an association between sleep problems during adolescence and the presence of musculoskeletal pain at a later stage. These findings are consistent with adult literature suggesting a link between sleep problems and musculoskeletal pain. Given these associations, sleep problems in adolescence may be an important risk factor for musculoskeletal pain.
PMCID: PMC4197758  PMID: 25299477
Adolescence; ALSPAC; Chronic pain; Sleep
21.  Extinction of cue-evoked drug-seeking relies on degrading hierarchical instrumental expectancies 
Behaviour Research and Therapy  2014;59(100):61-70.
There has long been need for a behavioural intervention that attenuates cue-evoked drug-seeking, but the optimal method remains obscure. To address this, we report three approaches to extinguish cue-evoked drug-seeking measured in a Pavlovian to instrumental transfer design, in non-treatment seeking adult smokers and alcohol drinkers. The results showed that the ability of a drug stimulus to transfer control over a separately trained drug-seeking response was not affected by the stimulus undergoing Pavlovian extinction training in experiment 1, but was abolished by the stimulus undergoing discriminative extinction training in experiment 2, and was abolished by explicit verbal instructions stating that the stimulus did not signal a more effective response-drug contingency in experiment 3. These data suggest that cue-evoked drug-seeking is mediated by a propositional hierarchical instrumental expectancy that the drug-seeking response is more likely to be rewarded in that stimulus. Methods which degraded this hierarchical expectancy were effective in the laboratory, and so may have therapeutic potential.
Highlights
•Reveals why drug cue extinction therapy has been clinically ineffective.•Provides laboratory validation of a more effective extinction method.•Clarifies the associative mechanisms underpinning drug cue reactivity & extinction.•Corroborates human and animal data.•Discusses the therapeutic potential of the new extinction method.
doi:10.1016/j.brat.2014.06.001
PMCID: PMC4119239  PMID: 25011113
Extinction; Learning; Transfer; Dependence; Relapse
22.  Phenotype Refinement Strengthens the Association of AHR and CYP1A1 Genotype with Caffeine Consumption 
PLoS ONE  2014;9(7):e103448.
Two genetic loci, one in the cytochrome P450 1A1 (CYP1A1) and 1A2 (CYP1A2) gene region (rs2472297) and one near the aryl-hydrocarbon receptor (AHR) gene (rs6968865), have been associated with habitual caffeine consumption. We sought to establish whether a more refined and comprehensive assessment of caffeine consumption would provide stronger evidence of association, and whether a combined allelic score comprising these two variants would further strengthen the association. We used data from between 4,460 and 7,520 women in the Avon Longitudinal Study of Parents and Children, a longitudinal birth cohort based in the United Kingdom. Self-report data on coffee, tea and cola consumption (including consumption of decaffeinated drinks) were available at multiple time points. Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption. There was no association with cola consumption, possibly due to low levels of consumption in this sample. There was also no association with measures of decaffeinated drink consumption, indicating that the observed association is most likely mediated via caffeine. The association was strengthened when a combined allelic score was used, accounting for up to 1.28% of phenotypic variance. This was not associated with potential confounders of observational association. A combined allelic score accounts for sufficient phenotypic variance in caffeine consumption that this may be useful in Mendelian randomization studies. Future studies may therefore be able to use this combined allelic score to explore causal effects of habitual caffeine consumption on health outcomes.
doi:10.1371/journal.pone.0103448
PMCID: PMC4116211  PMID: 25075865
23.  Maternal smoking during pregnancy and offspring smoking initiation: assessing the role of intrauterine exposure 
Addiction (Abingdon, England)  2014;109(6):1013-1021.
Aims
To assess whether associations between maternal smoking during pregnancy and offspring smoking initiation are due to intrauterine mechanisms.
Design
Comparison of associations of maternal and partner smoking behaviour during pregnancy with offspring smoking initiation using partner smoking as a negative control (n = 6484) and a Mendelian randomization analysis (n = 1020), using a genetic variant in the mothers as a proxy for smoking cessation during pregnancy.
Setting
A longitudinal birth cohort in South West England.
Participants
Participants of the Avon Longitudinal Study of Parents and Children (ALSPAC).
Measurements
Smoking status during pregnancy was self-reported by mother and partner in questionnaires administered at pregnancy. Latent classes of offspring smoking initiation (non-smokers, experimenters, late-onset regular smokers and early-onset regular smokers) were previously developed from questionnaires administered at 14–16 years. A genetic variant, rs1051730, was genotyped in the mothers.
Findings
Both mother and partner smoking were similarly positively associated with offspring smoking initiation classes, even after adjustment for confounders. Odds ratios (OR) [95% confidence interval (CI)] for class membership compared with non-smokers were: experimenters: mother OR = 1.33 (95% CI = 1.06, 1.67), partner OR = 1.28 (95% CI = 1.06, 1.55), late-onset regular smokers: mother OR = 1.80 (95% CI = 1.43, 2.26), partner OR = 1.86 (95% CI = 1.52, 2.28) and early-onset regular smokers: mother OR = 2.89 (95% CI = 2.12, 3.94), partner OR = 2.50 (95% CI = 1.85, 3.37). There was no clear evidence for a dose–response effect of either mother or partner smoking heaviness on class membership. Maternal rs1051730 genotype was not clearly associated with offspring smoking initiation class in pre-pregnancy smokers (P = 0.35).
Conclusion
The association between smoking during pregnancy and offspring smoking initiation does not appear to operate through intrauterine mechanisms.
doi:10.1111/add.12514
PMCID: PMC4114534  PMID: 24521169
ALSPAC; intrauterine; maternal smoking; Mendelian randomization; negative control; offspring smoking; pregnancy; tobacco
24.  Nicotine patch preloading for smoking cessation (the preloading trial): study protocol for a randomized controlled trial 
Trials  2014;15:296.
Background
The use of nicotine replacement therapy before quitting smoking is called nicotine preloading. Standard smoking cessation protocols suggest commencing nicotine replacement therapy only on the first day of quitting smoking (quit day) aiming to reduce withdrawal symptoms and craving. However, other, more successful smoking cessation pharmacotherapies are used prior to the quit day as well as after. Nicotine preloading could improve quit rates by reducing satisfaction from smoking prior to quitting and breaking the association between smoking and reward. A systematic literature review suggests that evidence for the effectiveness of preloading is inconclusive and further trials are needed.
Methods/Design
This is a study protocol for a multicenter, non-blinded, randomized controlled trial based in the United Kingdom, enrolling 1786 smokers who want to quit, funded by the National Institute for Health Research, Health Technology Assessment program, and sponsored by the University of Oxford. Participants will primarily be recruited through general practices and smoking cessation clinics, and randomized (1:1) either to use 21 mg nicotine patches, or not, for four weeks before quitting, whilst smoking as normal. All participants will be referred to receive standard smoking cessation service support.
Follow-ups will take place at one week, four weeks, six months and 12 months after quit day. The primary outcome will be prolonged, biochemically verified six-month abstinence. Additional outcomes will include point prevalence abstinence and abstinence of four-week and 12-month duration, side effects, costs of treatment, and markers of potential mediators and moderators of the preloading effect.
Discussion
This large trial will add substantially to evidence on the effectiveness of nicotine preloading, but also on its cost effectiveness and potential mediators, which have not been investigated in detail previously. A range of recruitment strategies have been considered to try and compensate for any challenges encountered in recruiting the large sample, and the multicentre design means that knowledge can be shared between recruitment teams. The pragmatic study design means that results will give a realistic estimate of the success of the intervention if it were to be rolled out as part of standard smoking cessation service practice.
Trial registration
Current Controlled Trials ISRCTN33031001. Registered 27 April 2012.
doi:10.1186/1745-6215-15-296
PMCID: PMC4223826  PMID: 25052334
Smoking; Nicotine; Preloading; Tobacco; Cessation; Quitting; Addiction; Treatment
25.  Plain packaging of cigarettes and smoking behavior: study protocol for a randomized controlled study 
Trials  2014;15:252.
Background
Previous research on the effects of plain packaging has largely relied on self-report measures. Here we describe the protocol of a randomized controlled trial investigating the effect of the plain packaging of cigarettes on smoking behavior in a real-world setting.
Methods/Design
In a parallel group randomization design, 128 daily cigarette smokers (50% male, 50% female) will attend an initial screening session and be assigned plain or branded packs of cigarettes to smoke for a full day. Plain packs will be those currently used in Australia where plain packaging has been introduced, while branded packs will be those currently used in the United Kingdom. Our primary study outcomes will be smoking behavior (self-reported number of cigarettes smoked and volume of smoke inhaled per cigarette as measured using a smoking topography device). Secondary outcomes measured pre- and post-intervention will be smoking urges, motivation to quit smoking, and perceived taste of the cigarettes. Secondary outcomes measured post-intervention only will be experience of smoking from the cigarette pack, overall experience of smoking, attributes of the cigarette pack, perceptions of the on-packet health warnings, behavior changes, views on plain packaging, and the rewarding value of smoking. Sex differences will be explored for all analyses.
Discussion
This study is novel in its approach to assessing the impact of plain packaging on actual smoking behavior. This research will help inform policymakers about the effectiveness of plain packaging as a tobacco control measure.
Trial registration
Current Controlled Trials ISRCTN52982308 (registered 27 June 2013).
doi:10.1186/1745-6215-15-252
PMCID: PMC4227078  PMID: 24965551
Smoking; Plain packaging; Standardized packaging; Randomized controlled trial; Health warnings; Smoking behavior

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