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Background and aims Previous studies suggest an association between maternal tobacco and caffeine consumption during and outside of pregnancy and offspring mental health. We aimed to separate effects of the maternal environment (intrauterine or postnatal) from pleiotropic genetic effects. Design Secondary analysis of a longitudinal study. We 1) validated smoking and caffeine genetic risk scores (GRS) derived from published GWAS for use during pregnancy, 2) compared estimated effects of maternal and offspring GRS on childhood mental health outcomes, and 3) tested associations between maternal and offspring GRS on their respective outcomes. Setting We used data from a longitudinal birth cohort study from England, the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants Our sample included 7921 mothers and 7964 offspring. Measurements Mental health and non-mental health phenotypes were derived from questionnaires and clinical assessments: 79 maternal phenotypes assessed during and outside of pregnancy, and 71 offspring phenotypes assessed in childhood ( Findings The maternal smoking and caffeine GRS were associated with maternal smoking and caffeine consumption during pregnancy (2nd trimester: Psmoking = 3.0×10−7, Pcaffeine = 3.28×10−5). Both the maternal and offspring smoking GRS showed evidence of association with reduced childhood anxiety symptoms (βmaternal = -0.033; βoffspring= -0.031) and increased conduct disorder symptoms (βmaternal= 0.024; βoffspring= 0.030), after correcting for multiple testing. Finally, the maternal and offspring smoking GRS were associated with phenotypes related to sensation seeking behaviours in mothers and adolescence (e.g., increased symptoms of externalising disorders, extraversion, and monotony avoidance). The caffeine GRS showed weaker evidence for associations with mental health outcomes. Conclusions We did not find strong evidence that maternal smoking and caffeine genetic risk scores (GRS) have a causal effect on offspring mental health outcomes. Our results confirm that the smoking GRS also captures liability for sensation seeking personality traits.

Background There are challenges in studying the effects of partner exposures around pregnancy on child health. We explored potential sources of bias in the effects of parental prenatal health behaviours on child health, to describe and quantify some of these challenges, as well as suggest ways in which they might be mitigated. Methods First, we characterised the availability of data on partner and mother health behaviours in the prenatal period from three UK cohort studies: the Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Millennium Cohort Study (MCS). Second, we assessed the potential for sample selection in these cohorts by comparing characteristics of families where the partner did and did not participate. Third, using parental smoking during pregnancy and child birthweight as an example, we ran simulation studies of several DAGs to explore the extent that missing partner data and selection can affect estimates. We then explored the ‘real life’ impact of partner sample selection on estimates of maternal effect. Results In all cohorts, data on partner prenatal health behaviours was less detailed and collected less frequently than maternal prenatal health behaviours. Partners participated in ALSPAC and MCS for the majority of pregnancies. Of 14,472 pregnancies in ALSPAC, and 18,241 pregnancies in MCS, 12,997 (78%) and 13,145 (71%) had a cohort participating partner, respectively. However, partner participation was much lower in BiB: 3131/11,538 pregnancies (27%) had a cohort participating partner. Consistently across all cohorts, in pregnancies with cohort participating partners, mothers were more likely to be living with their partner before birth of the child, be white and have a university degree. They were consistently less likely to have no qualifications and their babies were less likely to be born preterm or have a low birthweight. We saw relatively stable effect estimates within cohorts for associations between maternal smoking and offspring birthweight regardless of whether we used the full sample, the sample where fathers participated (selected either through stratification or adjusting for partner smoking), or the sample where fathers did not participate. Conclusion Overall, these results show partner selection is unlikely to cause strong selection bias in estimates of maternal effects. This suggests that, although inclusion of partner data with high levels of non-random missingness has the potential to introduce selection bias, in practice, the biasing effect appears to be small. This also has implications for studies of partner effects in their own right.

International audience; Since the beginning of the COVID-19 pandemic, discussions on social media and blogs have indicated that women have experienced menstrual changes, including altered menstrual duration, frequency, regularity, and volume (heavier bleeding and clotting), increased dysmenorrhea, and worsened premenstrual syndrome. There have been a small number of scientific studies of variable quality reporting on menstrual cycle features during the pandemic, but it is still unclear whether apparent changes are due to COVID-19 infection/illness itself, or other pandemic-related factors like increased psychological stress and changes in health behaviours. It is also unclear to what degree current findings are explained by reporting bias, recall bias, selection bias and confounding factors. Further research is urgently needed. We provide a list of outstanding research questions and potential approaches to address them. Findings can inform policies to mitigate against gender inequalities in health and society, allowing us to build back better post-COVID.

Previous cohort studies have observed higher birth order to be associated with increased risk of suicidal behaviour. However, the mechanisms underlying this association are unclear. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we used multivariable logistic regression models and mediation analysis to investigate the associations of birth order with adolescent suicide attempts and psychiatric disorder. We investigated whether the number of maternal depressive episodes and father absence mediated the associations found. In fully adjusted models (n = 2571), higher birth order was associated with an increased risk of both suicide attempts (OR = 1.42, CI = 1.10–1.84) and psychiatric disorder (OR = 1.29, CI = 0.99–1.69). Maternal depression and father absence only partially mediated (8%; 12%) these associations. Whilst maternal depression and paternal absence partially mediated the associations between birth order, and suicidal behaviour and psychiatric disorder, other pathways may account for much of these associations. Future studies should investigate alternative mediating pathways. Electronic supplementary material The online version of this article (10.1007/s00787-018-1266-1) contains supplementary material, which is available to authorized users.

The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the schizophrenia-associated ‘A’ allele (N = 22) or the alternative ‘C’ allele (N = 18) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequence task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation. Average MST learning and sleep-dependent performance improvements were similar across genotype groups, albeit more variable in the AA group. During sleep after learning, CC participants showed increased slow-wave (SW) and spindle amplitudes, plus augmented coupling of SW activity across recording electrodes. SW and spindles in those with the AA genotype were insensitive to learning, whilst SW coherence decreased following MST training. Accordingly, NREM neurophysiology robustly predicted the degree of overnight motor memory consolidation in CC carriers, but not in AA carriers. We describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in the coordinated neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of schizophrenia-associated common genetic variants on neural circuit oscillations and function.

Highlights • Alcohol PRS derived in the general population associated with consumption during pregnancy. • Maternal alcohol PRS associated with perinatal depression at 32 weeks gestation. • Maternal alcohol PRS associated with decreased offspring intellectual ability at age 13. • Offspring alcohol PRS did not predict offspring alcohol consumption in adolescence., Background Heavy alcohol consumption often co-occurs with mental health problems; this could be due to confounding, shared biological mechanisms, or causal effects. Polygenic risk scores (PRS) for alcohol use can be used to explore this association at critical life stages. Design We characterized a PRS reliably associated with patterns of adult alcohol consumption by 1) validating whether it predicts own alcohol use at different life-stages (pregnancy, adolescence) of interest for mental health impact. Additionally, we explored associations of alcohol PRS on mental health phenotypes 2) within-individuals (using own alcohol PRS on own phenotypes) and 3) intergenerationally (using maternal alcohol PRS on offspring phenotypes). We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 960–7841). Additional substance abuse behaviors and mental health/behavioral outcomes were investigated (alcohol phenotypes n = 22; health phenotypes n = 91). Findings Maternal alcohol PRS was associated with consumption during pregnancy (strongest signal: alcohol frequency at 18 weeks’ gestation: β = 0.041, 95%CI = 0.0.02–0.06), p = 1.01 × 10−5, adjusted R2 = 1.6 %), offspring alcohol PRS did not predict offspring alcohol consumption. We found evidence for an association of maternal alcohol PRS with own perinatal depression (OR = 1.10, 95% CI = 1.02 to 1.18, p = 0.022) and decreased offspring intellectual ability (β=-0.209, 95% CI -0.38 to -0.04, p= 0.016). Conclusions These alcohol PRS are a valid proxy for maternal alcohol use in pregnancy. Offspring alcohol PRS was not associated with drinking in adolescence. Consistently with results from different study designs, we found evidence that maternal alcohol PRS are associated with both prenatal depression and decreased offspring intellectual ability.

BackgroundThe rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia (SZ), yet brain and behavioral phenotypes related to this variant have not been extensively characterized. In turn, SZ is associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants.MethodsWe recruited healthy adult males, with no history of psychiatric disorder, from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the SZ-associated ‘A’ allele (N=25) or the alternative ‘C’ allele (N=22) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequencing task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation.ResultsAverage MST learning and sleep-dependent performance improvements were similar across genotype groups, but with increased variability in the AA group. CC participants showed increased slow-wave and spindle amplitudes, plus augmented coupling of slow-wave activity across recording electrodes after learning. Slow-waves and spindles in those with the AA genotype were insensitive to learning, whilst slow-wave coherence decreased following MST training.ConclusionWe describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in experience- and sleep-dependent, local and distributed neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of SZ-associated variants on neural circuit oscillations and function.

Background: Previous research has suggested that intrauterine alcohol exposure is associated with a variety of adverse outcomes in offspring. However, few studies have investigated its association with offspring internalising disorders in late adolescence. Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations of maternal drinking in pregnancy with offspring depression at age 18 and 24 (n = 13480). We also examined partner drinking as a negative control for intrauterine exposure for comparison.Results: Offspring of mothers that consumed any alcohol at 18 weeks gestation were at increased risk of having a diagnosis of depression (fully adjusted model: OR 1.17, 95% CI 1.02 to 1.34), but there was no clear evidence of association between partners alcohol consumption at 18 weeks gestation during pregnancy and increased risk of offspring depression (fully adjusted model: OR 0.87, 95% CI 0.74 to 1.01). Post-estimation tests found a positive difference between the association of maternal and partner alcohol use on offspring depression, showing a stronger association for maternal compared to partner alcohol use (OR 1.41, CI 1.07 to 1.84).Conclusions: Maternal drinking in pregnancy was associated with increased risk of offspring depression at age 18. Residual confounding may explain this association, but the negative control comparison of paternal drinking provides some evidence that it may be causal, and this warrants further investigation.

Background An emerging technique is a Phenome Wide Association Study (PheWAS), which reverses the phenotype to genotype methods used within a GWAS, instead taking a pre-determined set of genetic variants, and testing which of a wide range of phenotypes these genetic variants may be associated with. We can further investigate the genetic architecture of multiple traits and disease outcomes through linking a chosen genetic variant to multiple phenotypes, in varying populations. In this study we constructed polygenic risk scores (PRS) from single nucleotide polymorphisms (SNPs) shown to be robustly related to alcohol use, to test: These genetic signals within two sub populations of adolescents, and for pregnant women. If there are any associations (other than with alcohol use) of these PRS with many mental health phenotypes. Intrauterine effects of Maternal PRS for alcohol use for associations with offspring phenotypes. Methods Participants were mothers and offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were genotyped and PRS were constructed based on genome-wide significant SNPs for alcohol consumption. Targeted phenotypes were selected from substance use (n=22) and mental health/behavioural variables (n=91) within ALSPAC. Linear and logistic regression analyses were used to investigate if PRS for alcohol use were associated with alcohol use (mothers in pregnancy; children) and health phenotypes (mothers during pregnancy; children both pre-alcohol use around ages 7–10, and post-alcohol use around ages 13–23). Results The PRS were associated with multiple alcohol consumption phenotypes (strongest signal for alcohol amount at 18 weeks gestation: p=1.01×10-5) in pregnant mothers. There was an effect of maternal PRS for alcohol use on mother’s perinatal depression (p=0.02), offspring intellect (p=0.016), and ADHD (p=0.04). Discussion The effects of alcohol PRS previously found in the general population are also shown during pregnancy. We found an intrauterine effect of alcohol PRS on offspring intellect and ADHD. The effects shown are not due to offspring’s own alcohol use, as these effects were not found within the child’s analyses.

Background and Aims Despite a wealth of literature, the relationship between anxiety and alcohol use remains unclear. We examined whether (a) child and adolescent anxiety is positively or negatively associated with later alcohol use and disorders and (b) study characteristics explain inconsistencies in findings. Design and Setting We conducted a systematic review of 51 prospective cohort studies from 11 countries. Three studies contributed to a meta‐analysis. We searched PubMed, Scopus, Web of Science and PsycINFO databases, and studies were included if they met the following criteria: English language publication, human participants, anxiety exposure (predictor variable) in childhood or adolescence and alcohol outcome at least 6 months later. Participants Study sample sizes ranged from 110 to 11 157 participants. Anxiety exposure ages ranged from 3 to 24 years, and alcohol outcome ages ranged from 11 to 42 years. Measurements Ninety‐seven associations across 51 studies were categorized by anxiety exposure (generalized anxiety disorder, internalizing disorders, miscellaneous anxiety, obsessive compulsive disorder, panic disorder, separation anxiety disorder, social anxiety disorder and specific phobias) and alcohol use outcome (drinking frequency/quantity, binge drinking and alcohol use disorders). Findings The narrative synthesis revealed some evidence for a positive association between anxiety and later alcohol use disorders. Associations of anxiety with later drinking frequency/quantity and binge drinking were inconsistent. Type and developmental period of anxiety, follow‐up duration, sample size and confounders considered did not appear to explain the discrepant findings. The meta‐analysis also showed no clear evidence of a relationship between generalized anxiety disorder and later alcohol use disorder (odds ratio = 0.94, 95% confidence interval = 0.47–1.87). Conclusions Evidence to date is suggestive, but far from conclusive of a positive association between anxiety during childhood and adolescence and subsequent alcohol use disorder.

BackgroundNicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data.ObjectivesTo assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading.DesignOpen-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.SettingNHS smoking cessation clinics.ParticipantsPeople seeking help to stop smoking.InterventionsNicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators.Main outcome measuresThe primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model.ResultsIn total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) –0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62;p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73;p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI –£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving.LimitationsThe open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.ConclusionsUse of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication.Trial registrationCurrent Controlled Trials ISRCTN33031001.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

BackgroundPrevious research has suggested that intrauterine alcohol exposure is associated with a variety of adverse outcomes in offspring. However, few studies have investigated its association with offspring internalising disorders in late adolescence.MethodsUsing data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations of maternal drinking in pregnancy with offspring depression at age 18. We also examined partner drinking as a negative control for intrauterine exposure for comparison.ResultsOffspring of mothers that consumed any alcohol at 18 weeks gestation were at increased risk of having a diagnosis of depression (OR 1.15, 95% CI 1.00 to 1.32), but there was no clear evidence of association between partners alcohol consumption during pregnancy and increased risk of offspring depression (OR 0.90, 95% CI 0.78 to 1.04).ConclusionsMaternal drinking in pregnancy was associated with increased risk of offspring depression at age 18. Residual confounding may explain this association, but the negative control comparison of paternal drinking provides some evidence that it may be causal, and this warrants further investigation.

IntroductionReproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. Scientific claims should not gain credence because of the status or authority of their originator but by the replicability of their supporting evidence. Even research of exemplary quality may have irreproducible empirical findings because of random or systematic error.RationaleThere is concern about the rate and predictors of reproducibility, but limited evidence. Potentially problematic practices include selective reporting, selective analysis, and insufficient specification of the conditions necessary or sufficient to obtain the results. Direct replication is the attempt to recreate the conditions believed sufficient for obtaining a previously observed finding and is the means of establishing reproducibility of a finding with new data. We conducted a large-scale, collaborative effort to obtain an initial estimate of the reproducibility of psychological science.ResultsWe conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. There is no single standard for evaluating replication success. Here, we evaluated reproducibility using significance and P values, effect sizes, subjective assessments of replication teams, and meta-analysis of effect sizes. The mean effect size (r) of the replication effects (Mr = 0.197, SD = 0.257) was half the magnitude of the mean effect size of the original effects (Mr = 0.403, SD = 0.188), representing a substantial decline. Ninety-seven percent of original studies had significant results (P < .05). Thirty-six percent of replications had significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.ConclusionNo single indicator sufficiently describes replication success, and the five indicators examined here are not the only ways to evaluate reproducibility. Nonetheless, collectively these results offer a clear conclusion: A large portion of replications produced weaker evidence for the original findings despite using materials provided by the original authors, review in advance for methodological fidelity, and high statistical power to detect the original effect sizes. Moreover, correlational evidence is consistent with the conclusion that variation in the strength of initial evidence (such as original P value) was more predictive of replication success than variation in the characteristics of the teams conducting the research (such as experience and expertise). The latter factors certainly can influence replication success, but they did not appear to do so here. Reproducibility is not well understood because the incentives for individual scientists prioritize novelty over replication. Innovation is the engine of discovery and is vital for a productive, effective scientific enterprise. However, innovative ideas become old news fast. Journal reviewers and editors may dismiss a new test of a published idea as unoriginal. The claim that “we already know this” belies the uncertainty of scientific evidence. Innovation points out paths that are possible; replication points out paths that are likely; progress relies on both. Replication can increase certainty when findings are reproduced and promote innovation when they are not. This project provides accumulating evidence for many findings in psychological research and suggests that there is still more work to do to verify whether we know what we think we know.