The daily reciprocal associations between electroencephalography measured sleep and affect.

Self-report studies show that sleep and positive and negative affect are closely and bidirectionally linked. However, studies assessing sleep objectively yield more inconsistent results. This study assessed the reciprocal, daily relationship between sleep as measured with electroencephalography (EEG) and affect (measured in the evening) in a natural setting. We assessed sleep both on the macrolevel (i.e., rapid eye movement [REM] sleep and slow-wave sleep [SWS] duration) and on the microlevel (i.e., REM sleep fragmentation). In this study, 33 participants (i.e., healthy college students, mean [standard deviation] age 21.55 [3.73] years, 67% female) were followed for 2 weeks. Each participant wore an EEG headband for 15 nights and had polysomnography during 3 of the 15 nights providing 72 analysable nights of polysomnography and 271 analysable nights with the EEG headband. Every evening participants reported their momentary negative and positive affect. We examined the relationship between pre-sleep affect and the sleep variables, as well as the reverse relationship, with sleep variables predicting evening affect the next day. We detected that higher negative affect in the evening was related to more fragmented REM sleep. However, this result was only found with polysomnography and not with the EEG headband. No significant associations were found between affect and time spent in REM sleep and SWS. Overall, no support was found for the reciprocal association between negative and positive affect and EEG measured sleep. Only limited support was found for an association in one direction (i.e., evening negative affect was associated with more REM sleep fragmentation at night).

Is the Association Between Alcohol Consumption and Mental Well-Being in University Students Linear, Curvilinear or Absent?

Background: Both alcohol consumption and mental well-being problems have been found to be prevalent in higher educated students and often have severe consequences. However, previous findings of the association between these constructs are mixed, possibly because often linear models are fitted, while some theories suggest a curvilinear association between the two concepts. Objectives: To clarify previously mixed findings, the current study compared curvilinear and linear models for the relationship between alcohol consumption and mental well-being in university students. Because of potential gender differences in this relationship, these models were explored for females and males separately. Data from the first cross-sectional online survey wave of the Healthy Student Life project including 2,631 female and 998 male students was used. The Alcohol Use Disorders Identification Test-consumption was used to measure alcohol consumption. Mental well-being was assessed by six sub-concepts (i.e., depressive symptoms, anxiety, stress, life satisfaction, happiness, and self-rated mental health). Results: For females both linear (for anxiety, life satisfaction, and self-rated mental health) and curvilinear (for depression, stress, and happiness) associations were found, while for males no support for either curvilinear or linear models was found. Conclusions: Results should be interpreted with caution due to the small effect sizes in the relationships for females but may suggest that testing the curvilinear association between alcohol consumption and mental well-being is an important future endeavor.

Using Instrumental Variables to Measure Causation over Time in Cross-Lagged Panel Models.

Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated assessments. The lagged effects in a CLPM depend on the time interval between assessments, eventually becoming undetectable at longer intervals. To address this limitation, we incorporate instrumental variables (IVs) into the CLPM with two study waves and two variables. Doing so enables estimation of both the lagged (i.e., "distal") effects and the bidirectional cross-sectional (i.e., "proximal") effects at each wave. The distal effects reflect Granger-causal influences across time, which decay with increasing time intervals. The proximal effects capture causal influences that accrue over time and can help infer causality when the distal effects become undetectable at longer intervals. Significant proximal effects, with a negligible distal effect, would imply that the time interval is too long to estimate a lagged effect at that time interval using the standard CLPM. Through simulations and an empirical application, we demonstrate the impact of time intervals on causal inference in the CLPM and present modeling strategies to detect causal influences regardless of the time interval in a study. Furthermore, to motivate empirical applications of the proposed model, we highlight the utility and limitations of using genetic variables as IVs in large-scale panel studies.

Childhood obesity and adolescent follow-up depressive symptoms: exploring a moderated mediation model of body esteem and gender.

Obesity is a well-recognized risk factor for adolescent depressive symptoms, but mediating mechanisms of this association have scarcely been studied. This study is unique in examining an indirect pathway of this link via body esteem (BE) prospectively from childhood (8-12 years) to adolescence (13-18 years). In addition, potential gender moderation was examined. This study utilized data from a case-control study comparing 100 children with and without obesity matched on important confounders (age, gender, and socioeconomic status). Our findings provide support for the mediating role of BE in the link between childhood weight status and adolescent depressive symptoms at a 5-year follow-up. This mediation effect did not differ between boys and girls. The findings suggest the relevance of specifically targeting children's BE in preventive intervention programs among children with obesity to prevent future mental health problems.

Heritability of adult picky eating in the Netherlands.

Adult picky eating (APE), the rejection of familiar and unfamiliar foods leading to a diet with limited variety, is an understudied phenomenon which can have both physical and psychological negative consequences. The aetiology of individual differences in APE is understudied, although there is reason to believe that it is partly heritable. Therefore, we aimed to estimate the heritability of APE with data from the Netherlands Twin Register (n = 8016) with classical genetic structural equation modelling. In order to use these data, we firstly investigated whether a Food Preference Questionnaire (FPQ) could measure APE with a pre-registered prestudy. Adult participants (n = 414) filled in online questionnaires, including a FPQ and measures related to APE. Spearman's rho correlation quantified the relationship between different elements of the Dutch FPQ and different scores on measures of APE. Results of the prestudy showed that the mean liking score on the FPQ could be used to measure APE (ρ > .50). This measure was then used in the main study to estimate the heritability of APE. Results showed that broad-sense heritability for APE is 49 % (additive genetic effects 14 % (95 % CI [00, 38]) + dominance genetic effects 35 % (95 % CI [11, 52]), while the remaining variance is explained by unique environmental factors. Future studies may focus on uncovering the specific genetic and unique environmental factors that play a role in APE.

Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use.

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9436 participants (7795 European and 1641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 [Formula: see text]: cg22572071 near gene ADGRF1, cg15280358 in ADAM12, cg00813162 in ACTN1, and cg01101459 near LINC01132. Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated to APOBR. We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.

Prevalence and clustering of health behaviours and the association with socio-demographics and mental well-being in Dutch university students.

The college years represent a vulnerable period for developing health-risk behaviours (e.g., physical inactivity/unhealthy eating habits/substance use/problematic internet use/insufficient sleep). This study examined current health behaviour levels (RQ1), health behaviour classes (RQ2) and between-class differences in socio-demographics (RQ3) and mental well-being (RQ4) among Dutch university students (n = 3771). Participants (Mage = 22.7 (SD = 4.3); 71.2% female/27.3% male/1.5% other) completed an online survey (Oct-Nov 2021). Descriptive statistics (RQ1), Latent Class Analysis (RQ2), and Kruskal-Wallis/Chi-square tests (RQ3-4) were used. RQ1: Prevalence rates suggest that a subsequent proportion of the student sample engages in health-risk behaviours. RQ2: Four classes were identified: class 1 (n = 862) "Licit substance use health-risk group", class 2 (n = 435) "Illicit and licit substance use health-risk group", class 3 (n = 1876) "Health-protective group" and class 4 (n = 598) "Non-substance use health-risk group". RQ3: Class 1 represents relatively more international students and students in a steady relationship. Class 2 represents relatively more older/male/(pre-)master students and students living with roommates/in a steady relationship/with more financial difficulty. Class 3 represents relatively more younger/female students and students living with family/with lower Body Mass Index (BMI)/less financial difficulty. Class 4 represents relatively more younger/non-Western/international/bachelor students and students living with children/single/part of LGBTIQ+ community/with higher BMI. RQ4: Class 3 has significantly higher mental well-being while class 4 has significantly lower mental well-being, relative to the other classes. Above findings provide new insights which can help educational institutes and governments better understand the clustering of students' health behaviours and between-class differences in socio-demographics and mental well-being.

Adolescents' food intake changes during the COVID-19 pandemic: The moderating role of pre-pandemic susceptibility, COVID-19 related stressors, and the social food context.

Although insight in how adolescents' food intake is affected by the COVID-19 pandemic is critical, knowledge is limited. Hence, this longitudinal study (N = 691, Mage = 14.30, SDage = 0.62; 52.5% female) investigated changes in adolescents' unhealthy (sugar-sweetened beverages, sweet snacks, savoury snacks) and healthy (fruit and vegetables) food intake (in total, obtained from home, and from outside the home) from pre-pandemic (Spring 2019) to the first lockdown (Spring 2020) and to six months later (Fall 2020). Moreover, several moderating factors were assessed. Results showed that the intake of unhealthy and healthy food in total and obtained from outside the home decreased during the lockdown. Six months later, unhealthy food intake returned to pre-pandemic levels, while healthy food intake remained lower. COVID-19 stressful life events and maternal food intake further qualified these longer-term changes in intake of sugar-sweetened beverages and fruit and vegetables, respectively. Future work is warranted to elucidate longer-term COVID-19 effects on adolescents' food intake.

University students' (binge) drinking during COVID-19 lockdowns: An investigation of depression, social context, resilience, and changes in alcohol use.

RATIONALE: The first COVID-19 lockdown impacted the social life and behaviors of university students, such as alcohol use. While previous studies have reported changes in students' alcohol use during the lockdown, knowledge of risk groups like binge drinkers is limited. OBJECTIVE: The purpose of this study is to investigate how the first lockdown impacted the alcohol use of university students who were regular binge drinkers before the lockdown. METHODS: Cross-sectional data were used to explore self-reported changes in alcohol use and associated psychosocial effects in regular binge drinking versus regular drinking university students (N = 7355) during the first COVID-19 lockdown (Spring 2020) in the Netherlands. RESULTS: University students generally drank less alcohol and reduced binge drinking behaviors during the lockdown. Being a binge drinker who increased/maintained alcohol use, or a regular drinker who increased, was associated with older age, fewer servings of alcohol per week before COVID-19, higher contact with friends, and not living with parents. Among regular binge drinkers, men increased their alcohol use during the lockdown significantly more than women. Among regular drinkers, those with high depressive symptoms and low resilience had increased alcohol use. CONCLUSIONS: These findings give insight into significant changes in drinking behaviors among university students during the first COVID-19 lockdown. More importantly, it underscores the need to reckon vulnerable students considering drinking type and associated psychosocial variables for increasing or maintaining higher alcohol use during societal stress periods. In the present study, an unexpected at-risk group emerged among regular drinkers who increased alcohol use during the lockdown in association with their mental state (i.e., depression and resilience). As the COVID-19 pandemic, and the possibility of similar scenarios in the future, is still present in the current student life, specific preventive strategies and interventions should be targeted accordingly.

Interplay between genetic risk and the parent environment in adolescence and substance use in young adulthood: A TRAILS study.

Many adolescents start using tobacco, alcohol, and cannabis. Genetic vulnerability, parent characteristics in young adolescence, and interaction (GxE) and correlation (rGE) between these factors could contribute to the development of substance use. Using prospective data from the TRacking Adolescent Individuals' Lives Survey (TRAILS; N = 1,645), we model latent parent characteristics in young adolescence to predict young adult substance use. Polygenic scores (PGS) are created based on genome-wide association studies (GWAS) for smoking, alcohol use, and cannabis use. Using structural equation modeling we model the direct, GxE, and rGE effects of parent factors and PGS on young adult smoking, alcohol use, and cannabis initiation. The PGS, parental involvement, parental substance use, and parent-child relationship quality predicted smoking. There was GxE such that the PGS amplified the effect of parental substance use on smoking. There was rGE between all parent factors and the smoking PGS. Alcohol use was not predicted by genetic or parent factors, nor by interplay. Cannabis initiation was predicted by the PGS and parental substance use, but there was no GxE or rGE. Genetic risk and parent factors are important predictors of substance use and show GxE and rGE in smoking. These findings can act as a starting point for identifying people at risk.

The effect of a multi-component school-based social network intervention on children's body mass index: a four-arm intervention study.

Objective: Schools are considered an important setting for stimulating healthy weight. The current study is unique in examining effects of a multi-component school-based social network intervention on children's body mass index z-scores (zBMI).Methods: Four schools were randomly allocated to one of four conditions: a social network intervention using influence agents focusing on water consumption, physical activity, a combination of the two, or a passive control condition. Participants included a total of 201 6- to-11-year-old children (53.7% girls; Mage = 8.51, SDage = 0.93). At baseline, 149 (76.0%) participants had a healthy weight, 29 (14.8%) had overweight and 18 (9.2%) had obesity.Results: Linear mixed effect models indicated that a multi-component school-based social network intervention targeting both water consumption and physical activity was most effective in decreasing children's zBMI.Conclusion: This study suggests that schools can contribute to the intervention of childhood obesity-even without involving the parents-by targeting both children's water consumption and physical activity through influential peers, but more research is needed to identify mechanisms of change.

A longitudinal study on changes in food parenting practices during COVID-19 and the role of parental well-being.

The COVID-19 pandemic may negatively influence food parenting practices, also among parents of adolescents. Parental well-being (stress and depressive symptoms) may explain these COVID-19 related changes in food parenting practices (snack structure, healthy structure, modeling, autonomy support, and coercive control). However, most previous studies performed before or during the COVID-19 pandemic have been limited by cross-sectional designs. The aim of the current study among parents of adolescent children was twofold. First, we aimed to examine prospective differences in food parenting practices comparing the situation before and during COVID-19. Second, we aimed to examine both cross-sectional and longitudinal associations between parental well-being and the dimensions of food parenting, while additionally examining whether these prospective associations were more pronounced in parents who had experienced more COVID-19 stressful life events. Parents (N = 290; 74.9% female; at baseline: Mage = 46.9; SDage = 4.3) of adolescent children (at baseline: Mage = 14.3; SDage = 0.6) completed online surveys about parental well-being and food parenting twice: One year before the COVID-19 pandemic (spring 2019) and during the COVID-19 pandemic, 1.5 years after the first measurement (autumn 2020). In general, we found consistent evidence for an average decrease in food autonomy support and an increase in coercive control during COVID-19. However, parental well-being did not seem to explain (changes in) food parenting practices during COVID-19, also not in combination with stressful life events. Our findings suggest that, regardless of parental well-being, the general COVID-19 situation had some small negative influences on autonomy support and coercive control among parents of adolescents. These findings might be explained by parents being more often confronted with unhealthy eating occasions in the COVID-19 home context, triggering these negative parental responses.

The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond.

Cannabis is among the most widely consumed psychoactive substances worldwide. Individual differences in cannabis use phenotypes can partly be explained by genetic differences. Technical and methodological advances have increased our understanding of the genetic aetiology of cannabis use. This narrative review discusses the genetic literature on cannabis use, covering twin, linkage, and candidate-gene studies, and the more recent genome-wide association studies (GWASs), as well as the interplay between genetic and environmental factors. Not only do we focus on the insights that these methods have provided on the genetic aetiology of cannabis use, but also on how they have helped to clarify the relationship between cannabis use and co-occurring traits, such as the use of other substances and mental health disorders. Twin studies have shown that cannabis use is moderately heritable, with higher heritability estimates for more severe phases of use. Linkage and candidate-gene studies have been largely unsuccessful, while GWASs so far only explain a small portion of the heritability. Dozens of genetic variants predictive of cannabis use have been identified, located in genes such as CADM2, FOXP2, and CHRNA2. Studies that applied multivariate methods (twin models, genetic correlation analysis, polygenic score analysis, genomic structural equation modelling, Mendelian randomisation) indicate that there is considerable genetic overlap between cannabis use and other traits (especially other substances and externalising disorders) and some evidence for causal relationships (most convincingly for schizophrenia). We end our review by discussing implications of these findings and suggestions for future work.

The CADM2 Gene and Behavior: A Phenome-Wide Scan in UK-Biobank.

The cell adhesion molecule 2 (CADM2) gene has appeared among the top associations in a wide range of genome-wide association studies (GWASs). This study aims to: (1) examine how widespread the role of CADM2 is in behavioural traits, and (2) investigate trait-specific effects on CADM2 expression levels across tissues. We conducted a phenome-wide association study in UK Biobank (N = 12,211-453,349) on 242 psycho-behavioral traits, both at the SNP and the gene-level. For comparison, we repeated the analyses for other large (and high LD) genes. We found significant associations between CADM2 and 50 traits (including cognitive, risk taking, and dietary traits), many more than for the comparison genes. We show that many trait associations are reduced when taking geographical stratification into account. S-Predixcan revealed that CADM2 expression in brain tissues was significantly associated with many traits; highly significant effects were also observed for lung, mammary, and adipose tissues. In conclusion, this study shows that the role of CADM2 extends to a wide range of psycho-behavioral traits, suggesting these traits may share a common biological denominator.

The gene environment aetiology of freezing and its relationship with internalizing symptoms during adolescence.

BACKGROUND: The freezing response is a universal response to threat, linked to attentive immobility and action preparation. It is relevant for acute stress coping in animals and humans, and subtle deviations in toddler freezing duration (absence of, or excessively long reactions) have been linked to higher risk for internalizing symptoms in adolescence. Yet, while individual freezing tendencies are relatively stable throughout life, little is known about their gene-environment aetiology. METHODS: We investigated the heritability of toddler freezing in the Quebec Newborn Twin Study (QNTS; n=508 twins) by fitting behavioural genetic models to video-coded freezing responses during a robot confrontation. Furthermore, we examined the predictive associations between toddler freezing and internalizing symptoms (anxiety and depressive symptoms), as they unfold during adolescence (ages 12-19 years) using linear mixed-effects models. FINDINGS: Freezing was found to be moderately heritable (45% of the variance accounted for by genetic factors). The remaining variance was explained by unique environmental factors, including measurement error. No significant contribution of shared environmental factors was noted. Additionally, shorter freezing was associated with more internalizing symptoms in adolescence at trend level, a pattern that was significant for depressive but not anxiety symptoms. INTERPRETATION: Freezing is an adaptive coping mechanism in early childhood, which is partly driven by genetic factors. Crucially, the absence or shorter duration of these behaviours may signal vulnerability to depressive problems later in life. FUNDING: Canadian Institutes of Health Research and Research Fund of Quebec-Health and Society and Culture. Consolidator grant from the European Research Council (ERC_CoG-2017_772337).

Examining food intake similarities in adolescent best friend dyads using longitudinal Actor-Partner Interdependence Models.

Little is known about how adolescent best friends may affect each other's food intake. This study explored whether friendship selection and socialization mechanisms explained potential food intake similarities in adolescent reciprocated best friend dyads. We also tested whether socialization processes were moderated by dyad member's relative zBMI. Members of 145 same-gender best friendship dyads (56% female; Mage = 12.79; SDage = 0.61) reported on their intake of food obtained from home and from outside the home at the beginning and the end of the school year through food frequency questionnaires. Longitudinal Actor-Partner Interdependence Models results showed no indication of selection or socialization, and very limited evidence for the moderation of socialization processes by relative zBMI. These findings indicate that focusing on adolescent reciprocated best friends in dietary interventions may not be valuable.

The Prevalence of Overweight Status among Early Adolescents from Private Schools in Indonesia: Sex-Specific Patterns Determined by School Urbanization Level.

(1) Background: Few studies have investigated (demographic) correlates of (prevalent) overweight rates among early adolescents, especially from higher socioeconomic positions (SEP) in developing countries, such as Indonesia. The current study aims to fill this gap. (2) Methods: Participants included 411 adolescents from five private schools in Indonesia. Adolescents' weight and height were measured, and adolescents completed questionnaires on demographic factors (i.e., sex, school area, ethnicity, pocket money) and previous year dieting. (3) Results: Results showed that more than one-third of the sample was overweight, with higher rates among adolescent males (47%) than females (24%). Moreover, adolescents attending schools in urban areas (compared with suburban areas), and those reporting past dieting (compared with those reporting no dieting) had higher overweight rates. Ethnicity and the amount of pocket money were not related to overweight status. Finally, a clear sex-specific interaction was found involving school area, showing that males in urban areas had a significantly higher risk to be overweight, whereas this did not apply to females. (4) Conclusions: males from urban area private schools in Indonesia may be an important target group for future preventive overweight interventions.

[A cohort-comparison of food intake, lifestyle and social-emotional health of adolescents before and during the corona crisis]. / Een cohortvergelijking van eetgedrag, leefstijl en sociaal-emotionele gezondheid bij jongeren vóór en tijdens de coronacrisis.

The corona crisis can be considered a 'natural experiment', in which the social context has changed dramatically. It is largely unknown how adolescents respond to this, and which behaviors change. We have compared a cohort of ninth graders (N = 177, M age = 15.00) from secondary schools before the corona crisis (Spring 2019) with a demographically comparable group of ninth graders (N = 188, M age = 14.95) during the first lockdown (Spring 2020). We compared the domains food intake, lifestyle, and social-emotional health between both cohorts, and we examined the associations within and between the domains for both cohorts. Sweet snack intake from home, alcohol use, and loneliness were higher in the corona cohort compared to before the corona crisis (non-significant after correction). The intake of fruit from home, of sugar-sweetened beverages and unhealthy snacks from outside the home, and of moderate and vigorous physical activity occurred less frequently during the lockdown. Relationship satisfaction with parents, happiness, and stress from school were lower compared to before the lockdown. Smoking, stress at home, and relationship satisfaction with their best friend were equal in both cohorts. The pattern of associations within and between domains differed. More research is needed to delineate how resilient youth are on the long-term, and which youth need support to bounce back.

Student-, Study- and COVID-19-Related Predictors of Students' Smoking, Binge Drinking and Cannabis Use before and during the Initial COVID-19 Lockdown in The Netherlands.

Tobacco, alcohol and cannabis are commonly used among university students. However, student lives and their substance use have changed dramatically since the start of the COVID-19 pandemic. This study investigated the impact of COVID-19 on (trends in) weekly smoking, weekly binge drinking and weekly cannabis use in Dutch university students and investigated associated student-, study- and COVID-19-related characteristics. Between April and June 2020, several Dutch higher educational institutes invited their students to participate in an online survey. Data of 9967 students (Mage = 22.0 (SD = 2.6); Nfemale = 7008 (70.3%)) were available for analyses. Overall, weekly smoking remained stable (±11.5%), weekly binge drinking decreased (from 27.8% to 13.9%) and weekly cannabis use increased (from 6.7% to 8.6%). Male gender, not living with parents, being a bachelor student, having less financial resources and less adherence to the COVID-19 measures were found to increase the risk of substance use (before/during the first COVID-19 lockdown). Additionally, male gender, not living with parents, being a bachelor student, not being born in the Netherlands and having a student loan contributed to the likelihood of increased substance use during COVID-19. Patterns of characteristics contributing to the likelihood of decreased weekly substance use during COVID-19 were less clear. The risk factors male gender, not living with parents and being a bachelor student do not only contribute to the likelihood of using substances but also contribute to the likelihood of increased use during a lockdown. Prevention and intervention programs should especially target these risk groups.

Investigating the causal nature of the relationship of subcortical brain volume with smoking and alcohol use.

BACKGROUND: Structural variation in subcortical brain regions has been linked to substance use, including the most commonly used substances nicotine and alcohol. Pre-existing differences in subcortical brain volume may affect smoking and alcohol use, but there is also evidence that smoking and alcohol use can lead to structural changes. AIMS: We assess the causal nature of the complex relationship of subcortical brain volume with smoking and alcohol use, using bi-directional Mendelian randomisation. METHOD: Mendelian randomisation uses genetic variants predictive of a certain 'exposure' as instrumental variables to test causal effects on an 'outcome'. Because of random assortment at meiosis, genetic variants should not be associated with confounders, allowing less biased causal inference. We used summary-level data of genome-wide association studies of subcortical brain volumes (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus; n = 50 290) and smoking and alcohol use (smoking initiation, n = 848 460; cigarettes per day, n = 216 590; smoking cessation, n = 378 249; alcoholic drinks per week, n = 630 154; alcohol dependence, n = 46 568). The main analysis, inverse-variance weighted regression, was verified by a wide range of sensitivity methods. RESULTS: There was strong evidence that liability to alcohol dependence decreased amygdala and hippocampal volume, and smoking more cigarettes per day decreased hippocampal volume. From subcortical brain volumes to substance use, there was no or weak evidence for causal effects. CONCLUSIONS: Our findings suggest that heavy alcohol use and smoking can causally reduce subcortical brain volume. This adds to accumulating evidence that alcohol and smoking affect the brain, and likely mental health, warranting more recognition in public health efforts.