There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83–1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12–0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.
5-HTTLPR; Antidepressant; SSRI; Meta-analysis; Discontinuation
Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others.
We examined effects of d-amphetamine on processing of emotional facial expressions, and on the social behavior of talking. We predicted amphetamine would enhance attention, identification and responsivity to positive expressions, and that this in turn would predict increased talkativeness.
Over three sessions, 36 healthy normal adults received placebo, 10mg, and 20mg d-amphetamine under counterbalanced double-blind conditions. At each session we measured processing of happy, fearful, sad and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking.
Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine.
The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine.
amphetamine; emotional faces; attentional bias; social interaction; psychophysiology
The subjective measures used to study mood disorders in humans cannot be replicated in animals; however, the increasing application of objective neuropsychological methods provides opportunities to develop translational animal tasks. Here we describe a novel behavioral approach, which has enabled us to investigate similar affective biases in rodents. In our affective bias test (ABT), rats encounter two independent positive experiences—the association between food reward and specific digging substrate—during discrimination learning sessions. These are performed on separate days under either neutral conditions or during a pharmacological or affective state manipulation. Affective bias is then quantified using a preference test where both previously rewarded substrates are presented together and the rat's choices recorded. The absolute value of the experience is kept consistent and all other factors are counterbalanced so that any bias at recall can be attributed to treatment. Replicating previous findings from studies in healthy volunteers, we observe significant positive affective biases following acute treatment with typical (fluoxetine, citalopram, reboxetine, venlafaxine, clomipramine) and atypical antidepressants (agomelatine, mirtazapine), and significant negative affective biases following treatment with drugs associated with inducing negative affective states in humans (FG7142, rimonabant, 13-cis retinoic acid). We also observed that acute psychosocial stress and environmental enrichment induce significant negative and positive affective biases, respectively, and provide evidence that these affective biases involve memory consolidation. The positive and negative affective biases induced in our test also mirror the antidepressant and pro-depressant effects of these drugs in patients suggesting our test has both translational and predictive validity. Our results suggest that cognitive affective biases could contribute to drug- or stress-induced mood changes in people and support the hypothesis that a cognitive neuropsychological mechanism contributes to antidepressant drug efficacy.
affective bias; animal models; antidepressant; behavioral Science; mood/anxiety/stress disorders; pro-depressant; psychopharmacology; translational; depression; antidepressant; pro-depressant; affective bias; animal model
The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857–2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability (d'), and reaction time while controlling for important covariates. COMT genotype did not predict hits or d'. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance.
dopamine; cognition; learning & memory; neurogenetics; COMT genotype; executive functioning; ALSPAC; COMT genotype; executive functioning; working memory; genetics; ALSPAC
We have developed a new paradigm that targets the recognition of facial expression of emotions. Here we report the protocol of a randomised controlled trial of the effects of emotion recognition training on mood in a sample of individuals with depressive symptoms over a 6-week follow-up period.
We will recruit 190 adults from the general population who report high levels of depressive symptoms (defined as a score ≥ 14 on the Beck Depression Inventory-II). Participants will attend a screening session and will be randomised to intervention or control procedures, repeated five times over consecutive days (Monday to Friday). A follow-up session will take place at end-of -treatment, 2-weeks and 6-weeks after training. Our primary study outcome will be depressive symptoms, Beck Depression Inventory- II (rated over the past two weeks). Our secondary outcomes are: depressive symptoms, Hamilton Rating Scale for Depression; anxiety symptoms, Beck Anxiety Inventory (rated over the past month); positive affect, Positive and Negative Affect Schedule (rated as ‘how you feel right now’); negative affect, Positive and Negative Affect Schedule (rated as ‘how you feel right now’); emotion sensitivity, Emotion Recognition Task (test phase); approach motivation and persistence, the Fishing Game; and depressive interpretation bias, Scrambled Sentences Test.
This study is of a novel cognitive bias modification technique that targets biases in emotional processing characteristic of depression, and can be delivered automatically via computer, Internet or Smartphone. It therefore has potential to be a valuable cost-effective adjunctive treatment for depression which may be used together with more traditional psychotherapy, cognitive-behavioural therapy and pharmacotherapy.
Current Controlled Trials: ISRCTN17767674
Emotion recognition training; Mood; Depression
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Genetic association; replication; HuGENet; Meta-Analysis
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.
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.
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.
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.
5-HTTLPR; amygdala; fMRI; meta-analysis; serotonin transporter gene
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.
► Common variants of small effect contribute to psychiatric disease. ► Rare de novo mutations occur in the exons of patients with schizophrenia and autism. ► Effect sizes of loci influencing brain size are comparable to those of other phenotypes. ► The literature of imaging genetic studies contains many false positives. ► Studies on gene by environment interaction are mostly underpowered.
In this review we discuss recent developments in psychiatric genetics: on the one hand, studies using whole genome approaches (genome-wide association studies (GWAS) and exome sequencing) are coming close to finding genes and molecular variants that contribute to disease susceptibility; on the other candidate genes, such as the serotonin transporter, continue to dominate in genetic studies of brain imaging phenotypes and in protracted searches for gene by environment interactions. These two areas intersect, in that new information about genetic effects from whole genome approaches, should (but does not always) inform the single locus analyses.
Tobacco use is common and remains one of the leading causes of preventable death in developed countries. Smoking commonly begins in adolescence, and hence, it is important to understand how smoking behavior develops during this period.
In a U.K.-based birth cohort, we analyzed repeated measures of smoking frequency in a sample of 7,322 young adolescents. Latent class analysis was used to summarize the data, and the resulting classes of behavior were related to a range of smoking risk factors. Results from a complete case analysis were compared with estimation using full-information maximum likelihood (FIML) and estimation using multiple imputation (MI).
Fifty-three percent of the sample reported having smoked a whole cigarette by age 16 years. The longitudinal data were summarized by 4 distinct patterns of smoking initiation: nonsmokers (79.7%), experimenters (10.3%), late-onset regular smokers (5.5%), and early-onset regular smokers (4.5%). Social disadvantage, other substance use, conduct problems, and female sex were strongly related to being a regular smoker; however, no risk factors studied showed any strong or consistent association with experimentation. In the complete case sample, smoking prevalence was lower, and in addition, the association between different smoking patterns and covariates was often inconsistent with those obtained through FIML/MI.
Most young people have experimented with tobacco smoking by age 16 years, and regular smoking is established in a substantial minority characterized by social disadvantage, other substance, use and conduct disorder. Prevention strategies should focus on this subgroup as most children who experiment with tobacco do not progress to regular smoking.
Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response.
The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal.
Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured.
The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups.
The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement.
Nicotine withdrawal; Stress; Nicotine replacement; Cortisol
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.
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.
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.
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.
High levels of alcohol consumption and increases in heavy episodic drinking (binge drinking) are a growing public concern, due to their association with increased risk of personal and societal harm. Alcohol consumption has been shown to be sensitive to factors such as price and availability. The aim of this study was to explore the influence of glass shape on the rate of consumption of alcoholic and non-alcoholic beverages.
This was an experimental design with beverage (lager, soft drink), glass (straight, curved) and quantity (6 fl oz, 12 fl oz) as between-subjects factors. Social male and female alcohol consumers (n = 159) attended two experimental sessions, and were randomised to drink either lager or a soft drink from either a curved or straight-sided glass, and complete a computerised task identifying perceived midpoint of the two glasses (order counterbalanced). Ethical approval was granted by the Faculty of Science Research Ethics Committee at the University of Bristol. The primary outcome measures were total drinking time of an alcoholic or non-alcoholic beverage, and perceptual judgement of the half-way point of a straight and curved glass.
Participants were 60% slower to consume an alcoholic beverage from a straight glass compared to a curved glass. This effect was only observed for a full glass and not a half-full glass, and was not observed for a non-alcoholic beverage. Participants also misjudged the half-way point of a curved glass to a greater degree than that of a straight glass, and there was a trend towards a positive association between the degree of error and total drinking time.
Glass shape appears to influence the rate of drinking of alcoholic beverages. This may represent a modifiable target for public health interventions.
Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups.
The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias.
Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N=56,013).
From the total comparisons identified, a small magnitude effect was evident (d=.15; p<.00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (n=3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (d=.58; p<.00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (d=.61) compared with studies using nonclinical samples (d=.45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate.
These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed.
Delay discounting; Impulsivity; Addiction; Substance dependence; Alcohol; Tobacco; Nicotine; Stimulant; Opiate; Gambling; Meta-analysis
Inhalation of 7.5% CO2 increases anxiety and autonomic arousal in humans, and elicits fear behavior in animals. However, it is not known whether CO2 challenge in humans induces dysfunction in neurocognitive processes that characterize generalized anxiety, notably selective attention to environmental threat. Healthy volunteers completed an emotional antisaccade task in which they looked toward or away from (inhibited) negative and neutral stimuli during inhalation of 7.5% CO2 and air. CO2 inhalation increased anxiety, autonomic arousal, and erroneous eye movements toward threat on antisaccade trials. Autonomic response to CO2 correlated with hypervigilance to threat (speed to initiate prosaccades) and reduced threat inhibition (increased orienting toward and slower orienting away from threat on antisaccade trials) independent of change in mood. Findings extend evidence that CO2 triggers fear behavior in animals via direct innervation of a distributed fear network that mobilizes the detection of and allocation of processing resources toward environmental threat in humans.
CO2; anxiety; cognition; attention; emotion processing; antisaccade; cognition; biological psychiatry; mood; anxiety; stress disorders; psychopharmacology
The nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 on chromosome 15 has been the subject of a considerable body of research over recent years. Two highly correlated single nucleotide polymorphisms (SNPs) within this region—rs16969968 in CHRNA5 and rs1051730 in CHRNA3—have generated particular interest.
We reviewed the literature relating to SNPs rs16969968 and rs1051730 and smoking-related phenotypes, and clinical and preclinical studies, which shed light on the mechanisms underlying these associations.
Following the initial discovery of an association between this locus and smoking behavior, further associations with numerous phenotypes have been subsequently identified, including smoking-related behaviors, diseases, and cognitive phenotypes. Potential mechanisms thought to underlie these have also been described, as well as possible gene × environment interaction effects.
Perhaps counter to the usual route of scientific inquiry, these initial findings, based exclusively on human samples and strengthened by their identification through agnostic genome-wide methods, have led to preclinical research focused on determining the mechanism underlying these associations. Progress has been made using knockout mouse models, highlighting the importance of α5 nAChR subunits in regulating nicotine intake, particularly those localized to the habenula–interpeduncular nucleus pathway. Translational research seeking to evaluate the effect of nicotine challenge on brain activation as a function of rs16969968 genotype using neuroimaging technologies is now called for, which may point to new targets for novel smoking cessation therapies.
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.
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.
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).
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.
The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA.
Methods and Findings
We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference = 5.0%, 95% CI −0.9,10.8, p = 0.098). Motivation to make another quit attempt among those (n = 331) not abstinent at six months was not significantly different between groups (p = 0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference = 5.8%, 95% CI 1.0,10.7, p = 0.018).
Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation.
This study investigated the developmental course of autistic traits in a nationally-representative sample between ages 7 and 13.
The parents of 6,539 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, and 13. The phenotypic progression of autistic traits was assessed in the full sample and among high scoring individuals (e.g. top 10%, 5%). Gender, IQ, and overall behavior difficulties were examined as potentially relevant influences on autistic trait trajectories.
Autistic traits were highly stable in the general population, both overall and in high scoring groups. In the full sample, there was no change in mean SCDC scores for females between ages 7 and 13 (p=0.43). Male scores decreased slightly, but significantly, on the order of 0.1 standard deviations (p<0.001). There was no mean change in parent-rated autistic traits within any of the high scoring groups. IQ was not related to phenotypic progression; high parent-rated behavior problems predicted slight improvement in SCDC scores over the course of the study period among high scoring individuals (p<0.01).
These findings suggest that autistic traits are highly stable in the general population, even among individuals with the highest concentrations of autism-like behaviors. Phenotypic stability is consistent with expectations for individuals with ASD, providing further support for a phenomenological continuum across the clinical threshold. Moreover, the gap between female and male risk for autistic symptomology is consistent over time.
Autism spectrum disorders; autistic traits; longitudinal analysis; ALSPAC
Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that ‘one size fits all’ smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice.
New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach.
By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed.
The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.
Aims: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. Methods: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol-use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. Results: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. Conclusions: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence.
Variation in the CHRNA5-A3-B4 gene cluster is a promising candidate region for smoking behavior and has been linked to multiple smoking-related phenotypes (e.g., nicotine dependence) and diseases (e.g., lung cancer). Two single nucleotide polymorphisms (SNPs), rs16969968 in CHRNA5 and rs1051730 in CHRNA3, have generated particular interest.
We evaluated the published evidence for association between rs16969968 (k = 27 samples) and rs1051730 (k = 44 samples) SNPs with heaviness of smoking using meta-analytic techniques. We explored which SNP provided a stronger genetic signal and investigated study-level characteristics (i.e., ancestry, disease state) to establish whether the strength of association differed across populations. We additionally tested for small study bias and explored the impact of year of publication.
Results and Conclusions:
Meta-analysis indicated compelling evidence of an association between the rs1051730/rs16966968 variants and daily cigarette consumption (fixed effects: B = 0.91, 95% CI = 0.77, 1.06, p < .001; random effects: B = 1.01, 95% CI = 0.81, 1.22, p < .001), equivalent to a per-allele effect of approximately 1 cigarette/day. SNP rs1051730 was found to provide a stronger signal than rs16966968 in stratified analyses (pdiff = .028), although this difference was only qualitatively observed in the subset of samples that provided data on both SNPs. While the functional relevance of rs1051730 is unknown, it may be a strong tagging SNP for functional haplotypes in this region.