[Show abstract][Hide abstract] ABSTRACT: It is now clear that almost all complex traits have a highly polygenic component; that is, their genetic basis consists of relatively frequent risk alleles at a very large number of loci, each making a small contribution to variation, or disease susceptibility. This general conclusion appears to hold for intermediate phenotypes. Therefore, we should not expect these phenotypes to be associated with substantially larger effect sizes than conventional phenotypes. Instead, their usefulness is likely to lie in understanding the mechanism underpinning associations identified via genome-wide association studies of conventional phenotypes.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: AimsTo investigate the relationship between cannabis and tobacco use by age 15 and subsequent educational outcomes.DesignBirth cohort studySettingEnglandParticipantsThe sample was drawn from the Avon Longitudinal Study of Parents and Children; a core sample of 1,155 individuals had complete information on all the variables.MeasurementsMain exposures were cannabis and tobacco use at age 15 assessed in clinic by computer assisted questionnaire and serum cotinine. Main outcomes were performance in standardised assessments at 16 (Key Stage Four, GCSE) in English and mathematics (mean scores), completion of five or more assessments at grade C level or higher and leaving school having achieved no qualifications. Analyses were sequentially adjusted for multiple covariates using a hierarchical approach. Covariates considered were: maternal substance use (ever tobacco or cannabis use, alcohol use above recommended limits) ; life course socio-economic position (family occupational class, maternal education, family income); child sex; month and year of birth; child educational attainment prior to age 11 (Key Stage 2); child substance use (tobacco, alcohol and cannabis) prior to age 15 and child conduct disorder.FindingsIn fully adjusted models both cannabis and tobacco use at age 15 were associated with subsequent adverse educational outcomes. In general the dose response effect seen was consistent across all educational outcomes assessed. Weekly cannabis use was negatively associated with English GCSE results (Grade Point Difference [GPD], −5.93, 95% CI, −8.34, −3.53) and with mathematics GCSE results (GPD, −6.91, 95% CI, −9.92, −3.89). Daily tobacco smoking was negatively associated with English GCSE (GPD, −11.90, 95% CI, −13.47, −10.33) and with mathematics GCSE (GPD, −16.72, 95% CI, −18.57, −14.86). The greatest attenuation of these effects was seen on adjustment for other substance use and conduct disorder. Following adjustment tobacco appeared to have a consistently stronger effect than cannabis.Conclusions
Both cannabis and tobacco use in adolescence are strongly associated with subsequent adverse educational outcomes. Given the non-specific patterns of association seen and the attenuation of estimates on adjustment it is possible that these effects arise through non-causal mechanisms, although a causal explanation cannot be discounted. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background
Alcohol-related blackouts (ARBs) are reported by ~50% of drinkers. While much is known about the prevalence of ARBs in young adults and their cross-sectional correlates, there are few prospective studies regarding their trajectories over time during mid-adolescence. This paper reports latent trajectory classes of ARBs between age 15 and 19, along with predictors of those patterns.Methods
Latent class growth analysis (LCGA) was used to evaluate the pattern of occurrence of ARBs across 4 time points for 1,402 drinking adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multinomial regression analyses evaluated age-15 demography, substance-related items, externalizing characteristics, and estimated peer substance use as predictors of latent class membership.ResultsARBs were reported at age 15 in 30% and at age 19 in 74% of these subjects. Four latent trajectory classes were identified: Class 1 (5.1%) reported no blackouts; for Class 2 (29.5%), ARBs rapidly increased with age; for Class 3 (44.9%), blackouts slowly increased; and for Class 4 (20.5%), ARBs were consistently reported. Using Class 2 (rapid increasers) as the reference, predictors of class membership included female sex, higher drinking quantities, smoking, externalizing characteristics, and estimated peer substance involvement (pseudo R2 = 0.22).ConclusionsARBs were common and repetitive in these young subjects, and predictors of their trajectories over time involved multiple domains representing diverse characteristics.
Alcoholism Clinical and Experimental Research 12/2014; · 3.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many studies have explored associations between depression and facial emotion recognition (ER). However, these studies have used various paradigms and multiple stimulus sets, rendering comparisons difficult. Few studies have attempted to determine the magnitude of any effect and whether studies are properly powered to detect it. We conducted a meta-analysis to synthesize the findings across studies on ER in depressed individuals compared to controls.
Psychological Medicine 11/2014; · 5.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nicotine's effects on mood are thought to enhance its addictive potential. However, the mechanisms underlying the effects of nicotine on affect regulation have not been reliably demonstrated in human laboratory studies. We investigated the effects of abstinence (experiment one), and nicotine challenge and expectancy (experiment two) on attentional bias towards facial emotional stimuli differing in emotional valence.
Nicotine & Tobacco Research 10/2014; · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Background
This study tests whether the genetic predictor (CHRNA5 nicotine receptor gene variants) and an environmental risk factor (partner smoking) interact in the prediction of smoking reduction.
Subjects were from a community-based, longitudinal study of women (N = 1,856) who smoked before pregnancy, and a randomized comparative effectiveness smoking cessation trial (N = 1,065). Smoking reduction was defined as the trajectory of self-reported smoking quantities over time in the observational study, and as the trajectory of alveolar CO levels in the cessation trial.
In the pregnancy study, rs16969968 genotype and partner smoking status interacted such that the smoking reduction was lowest for expectant mothers with high genetic risk and partner smoking, and highest for those with high genetic risk but not partner smoking (interaction of genotype*partner smoking on smoking quantity trajectory slope β=0.071, 95%CI = 0.013, 0.13, p = 0.017). In the clinical trial, a similar interaction was found (interaction β=0.20, 95%CI = 0.049, 0.36, p = 0.010). Furthermore, these associations were moderated by pharmacotherapy such that the interactive relation of genetic and environmental factors occurred in the placebo group, but not in the active pharmacotherapy group (interaction of genotype*partner smoking*pharmacotherapy on CO trajectory slope β=-0.25, 95%CI = -0.42, -.091, p = 0.0023).
The CHRNA5 genetic risk synergized the effect of partner smoking, producing an especially low likelihood of successful smoking reduction in two complementary studies. This suggests that the genetic vulnerability may be mitigated by altering environmental factors. In addition, cessation pharmacotherapy neutralizes the increase in cessation failure associated with combined genetic and environmental risks, which has possible relevance to treatment algorithms.
Drug and Alcohol Dependence 10/2014; · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tobacco use remains the leading cause of preventable death worldwide. Establishing the genetic aetiology of tobacco use and dependence is an important first step in understanding the neurobiological mechanisms of tobacco use, and in turn the development of effective treatments. In addition, whilst the effects of tobacco use on a broad range of physical illnesses (e.g. lung cancer, respiratory disease, cardiovascular disease) are now well-established, the causal effects of tobacco use on a number of other outcomes remains to be established. Determining the causes and consequences of tobacco use therefore continues to be both a scientific and a public health priority. Here we review emerging methods in genetic research that allow stronger causal inferences to be drawn from observational data.
Current Psychiatry Reports 10/2014; 16(10):477. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimsTo gain insight into the potential impact of plain tobacco packaging policy, two experiments were undertaken to test whether ‘prototype’ plain compared with branded UK cigarette pack stimuli would differentially elicit instrumental tobacco-seeking in a nominal Pavlovian to instrumental transfer (PIT) procedure.Design, Setting, ParticipantsTwo experiments were undertaken at the University of Bristol UK, with a convenience sample of adult smokers (Experiment 1, n = 23, Experiment 2, n = 121).MeasurementIn both experiments, smokers were trained on a concurrent choice procedure in which two responses earned points for cigarettes and chocolate, respectively, before images of branded and plain packs were tested for capacity to elicit the tobacco-seeking response in extinction. The primary outcome was percentage choice of the tobacco- over the chocolate-seeking response in plain pack, branded pack and no-stimulus condition.FindingsBoth experiments found that branded packs primed a greater percentage of tobacco-seeking (overall mean = 62%) than plain packs (overall mean = 53%) and the no-stimulus condition (overall mean = 52%; ps.≤01, ŋp2s ≥.16), and that there was no difference in percentage tobacco-seeking between plain packs and the no-stimulus condition (ps.≥17, ŋp2s ≤.04). Plain tobacco packs showed an overall 9% reduction in the priming of a tobacco choice response compared to branded tobacco packs.Conclusions
Plain packaging may reduce smoking in current smokers by degrading cue-elicited tobacco-seeking.
[Show abstract][Hide abstract] ABSTRACT: 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
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Intermediate phenotypes are traits positioned somewhere between genetic variation and disease. They represent a target for attempts to find disease-associated genetic variants and elucidation of mechanisms. Psychiatry has been particularly enamoured with intermediate phenotypes, due to uncertainty about disease aetiology, inconclusive results in early psychiatric genetic studies, and their appeal relative to traditional diagnostic categories. In this review, we argue that new genetic findings are relevant to the question of the utility of these constructs. In particular, results from genome-wide association studies of psychiatric disorders now allow an assessment of the potential role of particular intermediate phenotypes. Based on such an analysis, as well as other recent results, we conclude that intermediate phenotypes are likely to be most valuable in understanding mechanism.
Trends in Neurosciences 09/2014; · 12.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Depressive symptoms and alcohol misuse contribute substantially to the global health burden. These phenotypes often manifest, and frequently co-occur, during adolescence. However, few studies have examined whether both baseline levels of depressive symptoms and change in symptoms are associated with alcohol outcomes. In addition, inconsistent findings could be due to sex differences or the use of different alcohol outcomes. Using data from a prospective population-based cohort in the UK, we estimated trajectories of depressive symptoms from 12 years 10 months to 17 years 10 months, separately for male and female participants. We assessed whether baseline and change in depressive symptoms were associated with use and harmful use of alcohol at 18 years 8 months. Among females, increasing depressive symptoms were associated with increased alcohol use; whilst for males, there was little evidence of this. When examining harmful levels of alcohol use, baseline levels of depressive symptoms in males were weakly related to later harmful alcohol use but this association was attenuated substantially through adjustment for confounders. In contrast, both baseline symptoms and increase in symptoms were associated with later harmful alcohol use in females and these associations were not diminished by confounder adjustment. Elevated depressive symptoms during adolescence are positively associated with increases in both use and harmful use of alcohol at 18 years 8 months. These findings differ between the sexes. Further research is needed to examine the mechanisms underlying the link between depressive symptoms and harmful alcohol use to identify potentially modifiable factors for intervention.
European Child & Adolescent Psychiatry 08/2014; · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New studies have substantially advanced our understanding of the genetic architecture of schizophrenia, but we are far from identifying the underlying mutations. We may require new approaches to understand the biological implications of insights into the genetics of psychiatric disease.