Assessing rates and predictors of cannabis-associated psychotic symptoms across observational, experimental and medical research.

Cannabis, one of the most widely used psychoactive substances worldwide, can give rise to acute cannabis-associated psychotic symptoms (CAPS). While distinct study designs have been used to examine CAPS, an overarching synthesis of the existing findings has not yet been carried forward. To that end, we quantitatively pooled the evidence on rates and predictors of CAPS (k = 162 studies, n = 210,283 cannabis-exposed individuals) as studied in (1) observational research, (2) experimental tetrahydrocannabinol (THC) studies, and (3) medicinal cannabis research. We found that rates of CAPS varied substantially across the study designs, given the high rates reported by observational and experimental research (19% and 21%, respectively) but not medicinal cannabis studies (2%). CAPS was predicted by THC administration (for example, single dose, Cohen's d = 0.7), mental health liabilities (for example, bipolar disorder, d = 0.8), dopamine activity (d = 0.4), younger age (d = -0.2), and female gender (d = -0.09). Neither candidate genes (for example, COMT, AKT1) nor other demographic variables (for example, education) predicted CAPS in meta-analytical models. The results reinforce the need to more closely monitor adverse cannabis-related outcomes in vulnerable individuals as these individuals may benefit most from harm-reduction efforts.

Prospective and Retrospective Measures of Child Maltreatment and Their Association With Psychopathology: A Systematic Review and Meta-Analysis.

Importance: Prospective and retrospective measures of childhood maltreatment identify largely different groups of individuals. However, it is unclear if these measures are differentially associated with psychopathology. Objective: To analyze the associations of prospective and retrospective measures of childhood maltreatment with psychopathology. Data Sources: Based on a preregistered protocol, Embase, PsycInfo, and MEDLINE were searched for peer-reviewed studies published by January 1, 2023, that measured the associations of prospective and retrospective measures of child maltreatment with psychopathology. Study Selection: Titles and abstracts of all articles captured by the search and full texts of potentially eligible studies were independently screened by 2 authors. Observational studies with measures of the association of prospective and retrospective measures of childhood maltreatment with psychopathology were included. Data Extraction and Synthesis: Multiple investigators independently extracted data. Multilevel random-effects meta-analyses were used to pool the results and test predictors of heterogeneity. Main Outcome and Measures: Associations between prospective or retrospective measures of child maltreatment and psychopathology, both unadjusted and adjusted (ie, the association between prospective measures of maltreatment and psychopathology adjusted for retrospective measures, and vice versa), and moderation of these associations by preselected variables. Results: The meta-analyses were based on 24 studies including 15 485 individuals (51.0% female; mean age, 21.3 years at retrospective report). Retrospective measures of childhood maltreatment showed stronger associations with psychopathology relative to prospective measures in both unadjusted analyses (retrospective measures: odds ratio [OR], 2.21; 95%, 1.94-2.42 vs prospective measures: OR, 1.56; 95% CI, 1.39-1.76) and adjusted analyses (retrospective measures: OR, 2.14; 95% CI, 1.90-2.42 vs prospective measures: OR, 1.27; 95% CI, 1.13-1.41). There was no statistically significant moderation of the unadjusted or adjusted associations between prospective measures of child maltreatment and psychopathology. The associations between retrospective measures and psychopathology were stronger when the assessment of psychopathology was based on self-reports and was focused on internalizing or emotional disorders. Conclusions and Relevance: Psychopathology is more strongly associated with retrospective measures-which capture the first-person, subjective appraisal of childhood events reflected in memory recall-compared to prospective measures-which essentially capture third-person accounts of such events. Maltreatment-related psychopathology may be driven by subjective interpretations of experiences, distressing memories, and associated schemas, which could be targeted by cognitive interventions.

Burden of Mental Disorders and Suicide Attributable to Childhood Maltreatment.

Importance: The proportion of mental disorders and burden causally attributable to childhood maltreatment is unknown. Objective: To determine the contribution of child maltreatment to mental health conditions in Australia, accounting for genetic and environmental confounding. Design, Setting, and Participants: This meta-analysis involved an epidemiological assessment accounting for genetic and environmental confounding between maltreatment and mental health and 3 cross-sectional national surveys: the Australian Child Maltreatment Study (ACMS) 2023, National Study of Mental Health and Well-being 2020-2022, and Australian Burden of Disease Study 2023. Causal estimates were derived on the association between childhood maltreatment and mental health conditions from a meta-analysis of quasi-experimental studies. This was combined with the prevalence of maltreatment from the ACMS to calculate the population attributable fraction (PAF). The PAF was applied to the number and burden of mental health conditions in Australia, sourced from 2 population-based, nationally representative surveys of Australians aged 16 to 85 years, to generate the number and associated burden of mental disorders attributable to child maltreatment. Exposure: Physical abuse, sexual abuse, emotional abuse, or neglect prior to age 18 years. Main Outcomes and Measures: Proportion and number of cases, years of life lost, years lived with disability, and disability-adjusted life-years of mental health conditions (anxiety, depression, harmful alcohol and drug use, self-harm, and suicide attempt) attributable to childhood maltreatment. Results: Meta-analytic estimates were generated from 34 studies and 54 646 participants and applied to prevalence estimates of childhood maltreatment generated from 8503 Australians. Childhood maltreatment accounted for a substantial proportion of mental health conditions, ranging from 21% (95% CI, 13%-28%) for depression to 41% (95% CI, 27%-54%) of suicide attempts. More than 1.8 million cases of depressive, anxiety, and substance use disorders could be prevented if childhood maltreatment was eradicated. Maltreatment accounted for 66 143 years of life lost (95% CI, 43 313-87 314), primarily through suicide, and 184 636 disability-adjusted life-years (95% CI, 109 321-252 887). Conclusions and Relevance: This study provides the first estimates of the causal contribution of child maltreatment to mental health in Australia. Results highlight the urgency of preventing child maltreatment to reduce the population prevalence and burden of mental disorders.

The relationship between type, timing and duration of exposure to adverse childhood experiences and adolescent self-harm and depression: findings from three UK prospective population-based cohorts.

BACKGROUND: Adverse childhood experiences (ACEs) are well-established risk factors for self-harm and depression. However, despite their high comorbidity, there has been little focus on the impact of developmental timing and the duration of exposure to ACEs on co-occurring self-harm and depression. METHODS: Data were utilised from over 22,000 children and adolescents participating in three UK cohorts, followed up longitudinally for 14-18 years: the Avon Longitudinal Study of Parents and Children (ALSPAC), the Millennium Cohort Study (MCS) and the Environmental Risk (E-Risk) Longitudinal Twin Study. Multinomial logistic regression models estimated associations between each ACE type and a four-category outcome: no self-harm or depression, self-harm alone, depression alone and self-harm with co-occurring depression. A structured life course modelling approach was used to examine whether the accumulation (duration) of exposure to each ACE, or a critical period (timing of ACEs) had the strongest effects on self-harm and depression in adolescence. RESULTS: The majority of ACEs were associated with co-occurring self-harm and depression, with consistent findings across cohorts. The importance of timing and duration of ACEs differed across ACEs and across cohorts. For parental mental health problems, longer duration of exposure was strongly associated with co-occurring self-harm and depression in both ALSPAC (adjusted OR: 1.18, 95% CI: 1.10-1.25) and MCS (1.18, 1.11-1.26) cohorts. For other ACEs in ALSPAC, exposure in middle childhood was most strongly associated with co-occurring self-harm and depression, and ACE occurrence in early childhood and adolescence was more important in the MCS. CONCLUSIONS: Efforts to mitigate the impact of ACEs should start in early life with continued support throughout childhood, to prevent long-term exposure to ACEs contributing to risk of self-harm and depression in adolescence.

Editorial Perspective: Misaligned incentives in mental health research - the case for Registered Reports.

Current incentive structures reward mental health researchers for producing positive, novel, and clean results. This can promote questionable research practices which contribute to a distorted evidence base, in turn limiting progress in mental health research. Registered Reports (RRs) offer a solution to realign the incentives towards conducting high-quality, rigorous, and accurate studies, by preventing publication and reporting biases. However, the uptake of RRs in mental health research has so far been limited. This editorial perspective highlights the advantages of RRs for mental health research, before discussing potential challenges and how they can be addressed. Greater uptake of RRs in mental health research could help to promote a fairer research culture, limit publication bias and questionable research practices, and ultimately, improve understanding of mental health.

Independent Prediction of Child Psychiatric Symptoms by Maternal Mental Health and Child Polygenic Risk Scores.

OBJECTIVE: Prenatal maternal symptoms of depression and anxiety are associated with an increased risk for child socioemotional and behavioral difficulties, supporting the fetal origins of mental health hypothesis. However, to date, studies have not considered specific genomic risk as a possible confound. METHOD: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 5,546) was used to test if child polygenic risk score for attention-deficit/hyperactivity disorder (ADHD), schizophrenia, or depression confounds or modifies the impact of prenatal maternal depression and anxiety on child internalizing, externalizing, and total emotional/behavioral symptoms from age 4 to 16 years. Longitudinal child and adolescent symptom data were analyzed in the ALSPAC cohort using generalized estimating equations. Replication analyses were done in an independent cohort (Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] cohort; n = 514) from Finland, which provided complementary measures of maternal mental health and child psychiatric symptoms. RESULTS: Maternal depression and anxiety and child polygenic risk scores independently and additively predicted behavioral and emotional symptoms from childhood through mid-adolescence. There was a robust prediction of child and adolescent symptoms from both prenatal maternal depression (generalized estimating equation estimate = 0.093, 95% CI 0.065-0.121, p = 2.66 × 10-10) and anxiety (generalized estimating equation estimate = 0.065, 95% CI 0.037-0.093, p = 1.62 × 10-5) after adjusting for child genomic risk for mental disorders. There was a similar independent effect of maternal depression (B = 0.156, 95% CI 0.066-0.246, p = .001) on child symptoms in the PREDO cohort. Genetically informed sensitivity analyses suggest that shared genetic risk only partially explains the reported association between prenatal maternal depression and offspring mental health. CONCLUSION: These findings highlight the genomic contribution to the fetal origins of mental health hypothesis and further evidence that prenatal maternal depression and anxiety are robust in utero risks for child and adolescent psychiatric symptoms.

Improving the Way that We Conceptualise Adverse Childhood Experiences - A Commentary on Sisitsky et al. (2023).

Research on adverse childhood experiences (ACEs) has traditionally relied on cumulative ACE scores, which prevents understanding about the effects of distinct adversities and their mechanistic pathways. Dimensional and person-centred approaches have been proposed as alternative methods to conceptualise ACEs, which address limitations of the cumulative ACE score. In this issue, Sisitsky et al. (Research on Child and Adolescent Psychopathology, 2023) apply these approaches to identify dimensions of ACEs and profiles of children with distinct patterns of early exposure, in a large, racially diverse cohort from the US. The authors also examine the longitudinal associations between profiles of early adversity in early childhood with later mental health and telomere length. In this commentary, we discuss key findings from the study and recommend future avenues for improving the conceptualisation of ACEs.

Subjective and objective experiences of childhood adversity: a meta-analysis of their agreement and relationships with psychopathology.

BACKGROUND: Researchers use both subjective self-report and objective measures, such as official records, to investigate the impact of childhood adversity on psychopathology. However, it is unclear whether subjective and objective measures of childhood adversity (a) show agreement, and (b) differentially predict psychopathology. METHOD: To address this, we conducted a pre-registered meta-analysis to examine the agreement between subjective and objective measures of childhood adversity, and their prediction of psychopathology. We searched in PubMed, PsycINFO and Embase for articles with both subjective measures (self-reports) and objective measures of childhood adversity (comprising official records, or reports from multiple informants unrelated to the target individual), and measures of psychopathology. RESULTS: We identified 22 studies (n = 18,163) with data on agreement between subjective and objective measures of childhood adversities, and 17 studies (n = 14,789) with data on the associations between subjective and objective measures with psychopathology. First, we found that subjective and objective measures of childhood adversities were only moderately correlated (e.g. for maltreatment, r = .32, 95% CI = 0.23-0.41). Second, subjective measures of childhood adversities were associated with psychopathology, independent of objective measures (e.g. for maltreatment, r = .16, 95% CI = 0.09-0.22). In contrast, objective measures of childhood adversities had null or minimal associations with psychopathology, independent of subjective measures (e.g. r for maltreatment = .06, 95% CI = -0.02-0.13). CONCLUSIONS: Our findings suggest that the effects of childhood adversity on psychopathology are primarily driven by a person's subjective experience. If this is the case, clinical interventions targeting memories and cognitive processes surrounding childhood adversity may reduce the risk of psychopathology in exposed individuals.

Gene-environment correlations and genetic confounding underlying the association between media use and mental health.

The increase in online media use and mental health problems have prompted investigations into their association, although most literature is focussed on deleterious effects. We assessed the aetiology of media use and mental health associations (M age = 22.14, SD = 0.85) using twin (n = 4000 pairs) and polygenic score methods (n = 6000 unrelated individuals) in the Twins Early Development Study. Beyond the traditionally explored negative uses of online media (online victimisation and problematic internet use), we investigate general media uses such as posting online and watching videos and distinguish both positive (pro-social behaviour) and negative (anxiety, depression, peer and behaviour problems) mental health measures. Negative media use correlated with poor mental health (r = 0.11-0.32), but general media use correlated with prosocial behaviour (r = 0.20) and fewer behavioural problems (r = - 0.24). Twin analyses showed that both general and negative media use were moderately heritable (ranging from 20 to 49%) and their associations with mental health were primarily due to genetic influences (44-88%). Genetic sensitivity analysis combining polygenic scores with heritability estimates also suggest genetic confounding. Results indicate research on the mental health impact of media use should adopt genetically informed designs to strengthen causal inference.

Childhood Maltreatment and Mental Health Problems: A Systematic Review and Meta-Analysis of Quasi-Experimental Studies.

OBJECTIVE: Childhood maltreatment is associated with mental health problems, but the extent to which this relationship is causal remains unclear. To strengthen causal inference, the authors conducted a systematic review and meta-analysis of quasi-experimental studies examining the relationship between childhood maltreatment and mental health problems. METHODS: A search of PubMed, PsycINFO, and Embase was conducted for peer-reviewed, English-language articles from database inception until January 1, 2022. Studies were included if they examined the association between childhood maltreatment and mental health problems using a quasi-experimental method (e.g., twin/sibling differences design, children of twins design, adoption design, fixed-effects design, random-intercept cross-lagged panel model, natural experiment, propensity score matching, or inverse probability weighting). RESULTS: Thirty-four quasi-experimental studies were identified, comprising 54,646 independent participants. Before quasi-experimental adjustment for confounding, childhood maltreatment was moderately associated with mental health problems (Cohen's d=0.56, 95% CI=0.41, 0.71). After quasi-experimental adjustment, a small association between childhood maltreatment and mental health problems remained (Cohen's d=0.31, 95% CI=0.24, 0.37). This adjusted association between childhood maltreatment and mental health was consistent across different quasi-experimental methods, and generalized across different psychiatric disorders. CONCLUSIONS: These findings are consistent with a small, causal contribution of childhood maltreatment to mental health problems. Furthermore, the findings suggest that part of the overall risk of mental health problems in individuals exposed to maltreatment is due to wider genetic and environmental risk factors. Therefore, preventing childhood maltreatment and addressing wider psychiatric risk factors in individuals exposed to maltreatment could help to prevent psychopathology.

Early risk factors for joint trajectories of bullying victimisation and perpetration.

Bullying victimisation is a prevalent stressor associated with serious health problems. To inform intervention strategies, it is important to understand children's patterns of involvement in bullying victimisation and perpetration across development, and identify early risk factors for these developmental trajectories. We analysed data from the Millennium Cohort Study (N = 14,525; 48.6% female, 82.6% White), a representative birth cohort of British children born in 2000-2002 across the UK. Bullying victimisation and perpetration were assessed via child, mother, and teacher reports at ages 5, 7, 11, and 14 years. Early risk factors (child emotional, cognitive, and physical vulnerabilities, and adverse family environments) were assessed at ages 9 months, 3, and 5 years. Using k-means for longitudinal data, we identified five joint trajectories of victimisation and perpetration across ages 5, 7, 11, and 14: uninvolved children (59.78%), early child victims (9.96%), early adolescent victims (15.07%), early child bullies (8.01%), and bully- victims (7.19%). Individual vulnerabilities (e.g., emotional dysregulation, cognitive difficulties) and adverse family environments (maternal psychopathology, low income) in pre-school years independently forecast multiple trajectories of bullying involvement. Compared to victims, bully-victims were more likely to be male, have cognitive difficulties, and experience harsh discipline and low income. Interventions addressing these risk factors (e.g., via accessible mental health care, stigma-based interventions, or programs to support low-income families) may help to prevent bullying involvement and its associated sequelae.

A genetically informed Registered Report on adverse childhood experiences and mental health.

Children who experience adversities have an elevated risk of mental health problems. However, the extent to which adverse childhood experiences (ACEs) cause mental health problems remains unclear, as previous associations may partly reflect genetic confounding. In this Registered Report, we used DNA from 11,407 children from the United Kingdom and the United States to investigate gene-environment correlations and genetic confounding of the associations between ACEs and mental health. Regarding gene-environment correlations, children with higher polygenic scores for mental health problems had a small increase in odds of ACEs. Regarding genetic confounding, elevated risk of mental health problems in children exposed to ACEs was at least partially due to pre-existing genetic risk. However, some ACEs (such as childhood maltreatment and parental mental illness) remained associated with mental health problems independent of genetic confounding. These findings suggest that interventions addressing heritable psychiatric vulnerabilities in children exposed to ACEs may help reduce their risk of mental health problems.

Research Review: A guide to computing and implementing polygenic scores in developmental research.

The increasing availability of genotype data in longitudinal population- and family-based samples provides opportunities for using polygenic scores (PGS) to study developmental questions in child and adolescent psychology and psychiatry. Here, we aim to provide a comprehensive overview of how PGS can be generated and implemented in developmental psycho(patho)logy, with a focus on longitudinal designs. As such, the paper is organized into three parts: First, we provide a formal definition of polygenic scores and related concepts, focusing on assumptions and limitations. Second, we give a general overview of the methods used to compute polygenic scores, ranging from the classic approach to more advanced methods. We include recommendations and reference resources available to researchers aiming to conduct PGS analyses. Finally, we focus on the practical applications of PGS in the analysis of longitudinal data. We describe how PGS have been used to research developmental outcomes, and how they can be applied to longitudinal data to address developmental questions.

Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes.

BACKGROUND: Genetic influences are ubiquitous as virtually all phenotypes and most exposures typically classified as environmental have been found to be heritable. A polygenic score summarises the associations between millions of genetic variants and an outcome in a single value for each individual. Ever lowering costs have enabled the genotyping of many samples relevant to child psychology and psychiatry research, including cohort studies, leading to the proliferation of polygenic score studies. It is tempting to assume that associations detected between polygenic scores and phenotypes in those studies only reflect genetic effects. However, such associations can reflect many pathways (e.g. via environmental mediation) and biases. METHODS: Here, we provide a comprehensive overview of the many reasons why associations between polygenic scores, environmental exposures, and phenotypes exist. We include formal representations of common analyses in polygenic score studies using structural equation modelling. We derive biases, provide illustrative empirical examples and, when possible, mention steps that can be taken to alleviate those biases. RESULTS: Structural equation models and derivations show the many complexities arising from jointly modelling polygenic scores with environmental exposures and phenotypes. Counter-intuitive examples include that: (a) associations between polygenic scores and phenotypes may exist even in the absence of direct genetic effects; (b) associations between child polygenic scores and environmental exposures can exist in the absence of evocative/active gene-environment correlations; and (c) adjusting an exposure-outcome association for a polygenic score can increase rather than decrease bias. CONCLUSIONS: Strikingly, using polygenic scores may, in some cases, lead to more bias than not using them. Appropriately conducting and interpreting polygenic score studies thus requires researchers in child psychology and psychiatry and beyond to be versed in both epidemiological and genetic methods or build on interdisciplinary collaborations.

Genetic and early environmental predictors of adulthood self-reports of trauma.

BACKGROUND: Retrospective self-reports of childhood trauma are associated with a greater risk of psychopathology in adulthood than prospective measures of trauma. Heritable reporter characteristics are anticipated to account for part of this association, whereby genetic predisposition to certain traits influences both the likelihood of self-reporting trauma and of developing psychopathology. However, previous research has not considered how gene-environment correlation influences these associations. AIMS: To investigate reporter characteristics associated with retrospective self-reports of childhood trauma and whether these associations are accounted for by gene-environment correlation. METHOD: In 3963 unrelated individuals from the Twins Early Development Study, we tested whether polygenic scores for 21 psychiatric, cognitive, anthropometric and personality traits were associated with retrospectively self-reported childhood emotional and physical abuse. To assess the presence of gene-environment correlation, we investigated whether these associations remained after controlling for composite scores of environmental adversity across development. RESULTS: Retrospectively self-reported childhood trauma was associated with polygenic scores for autism spectrum disorder (ASD), body mass index (BMI), post-traumatic stress disorder (PTSD) and risky behaviours. When composite scores of environmental adversity were controlled for, only associations with the polygenic scores for ASD and PTSD remained significant. CONCLUSIONS: Genetic predisposition to ASD and PTSD may increase liability to experiencing or interpreting events as traumatic. Associations between genetic predisposition for risky behaviour and BMI with self-reported childhood trauma may reflect gene-environment correlation. Studies of the association between retrospectively self-reported childhood trauma and later-life outcomes should consider that genetically influenced reporter characteristics may confound associations, both directly and through gene-environment correlation.

Protecting against researcher bias in secondary data analysis: challenges and potential solutions.

Analysis of secondary data sources (such as cohort studies, survey data, and administrative records) has the potential to provide answers to science and society's most pressing questions. However, researcher biases can lead to questionable research practices in secondary data analysis, which can distort the evidence base. While pre-registration can help to protect against researcher biases, it presents challenges for secondary data analysis. In this article, we describe these challenges and propose novel solutions and alternative approaches. Proposed solutions include approaches to (1) address bias linked to prior knowledge of the data, (2) enable pre-registration of non-hypothesis-driven research, (3) help ensure that pre-registered analyses will be appropriate for the data, and (4) address difficulties arising from reduced analytic flexibility in pre-registration. For each solution, we provide guidance on implementation for researchers and data guardians. The adoption of these practices can help to protect against researcher bias in secondary data analysis, to improve the robustness of research based on existing data.

Poor Individual Risk Classification From Adverse Childhood Experiences Screening.

INTRODUCTION: Adverse childhood experiences confer an increased risk for physical and mental health problems across the population, prompting calls for routine clinical screening based on reported adverse childhood experience exposure. However, recent longitudinal research has questioned whether adverse childhood experiences can accurately identify ill health at an individual level. METHODS: Revisiting data collected for the Adverse Childhood Experience Study between 1995 and 1997, this study derived approximate area under the curve estimates to test the ability of the retrospectively reported adverse childhood experience score to discriminate between adults with and without a range of common health risk factors and disease conditions. Furthermore, the classification accuracy of a recommended clinical definition for high-risk exposure (≥4 versus 0-3 adverse childhood experiences) was evaluated on the basis of sensitivity, specificity, positive and negative predictive values, and positive likelihood ratios. RESULTS: Across all health outcomes, the levels of discrimination for the continuous adverse childhood experience score ranged from very poor to fair (area under the curve=0.50-0.76). The binary classification of ≥4 versus 0-3 adverse childhood experiences yielded high specificity (true-negative detection) and negative predictive values (absence of ill health among low-risk adverse childhood experience groups). However, sensitivity (true-positive detection) and positive predictive values (presence of ill health among high-risk adverse childhood experience groups) were low, whereas positive likelihood ratios suggested only minimal-to-moderate increases in health risks among individuals reporting ≥4 adverse childhood experiences versus that among those reporting 0-3. CONCLUSIONS: These findings suggest that screening based on the adverse childhood experience score does not accurately identify those individuals at high risk of health problems. This can lead to both allocation of unnecessary interventions and lack of provision of necessary support.

Adverse childhood experiences, daytime salivary cortisol, and depressive symptoms in early adulthood: a longitudinal genetically informed twin study.

Dysregulated hypothalamic-pituitary-adrenal (HPA)-axis function might underlie the relationship between adverse childhood experiences (ACEs) and depression. However, limited research has examined the possible mediating role of the HPA-axis among young people using longitudinal data. Moreover, it remains unclear whether genetic influences could contribute to these associations. Participants were 290 children from the Twins Early Development Study. ACEs were assessed from age 3-11 years. We calculated a cumulative risk score and also derived different ACEs clusters using factor analysis and latent class analysis. HPA-axis activity was indexed by daytime salivary cortisol at age 11. Depressive symptoms were ascertained at age 21. Genetic liability to altered cortisol levels and elevated depressive symptoms was measured using a twin-based method. We performed causal mediation analysis with mixed-effects regression models. The results showed that ACEs cumulative exposure (b = -0.20, p = 0.03), bullying (b = -0.61, p = 0.01), and emotional abuse (b = -0.84, p = 0.02) were associated with lower cortisol levels at age 11. Among participants exposed to multiple ACEs, lower cortisol was related to higher depressive symptoms at age 21 (b = -0.56, p = 0.05). Lower cortisol levels mediated around 10-20% of the total associations of ACEs cumulative exposure, bullying, and dysfunctional parenting/emotional abuse with higher depressive symptoms. Genetic factors contributed to these associations, but the mediation effects of cortisol in the associations of ACEs cumulative exposure (b = 0.16 [0.02-0.34]) and bullying (b = 0.18 [0.01-0.43]) remained when genetic confounding was accounted for. In conclusion, ACEs were linked to elevated depressive symptoms in early adulthood partly through lower cortisol levels in early adolescence, and these relationships were independent of genetic confounding.