Main findings

To our knowledge, this is the first study to delineate mediators of the relationship between childhood maltreatment and neuropsychiatric disorders. We replicated causal associations between childhood maltreatment and ADHD, MDD and schizophrenia from previous Mendelian randomisation studies. ^{Reference Warrier, Kwong, Luo, Dalvie, Croft and Sallis1,Reference Alkema, Marchi, van der Zaag, van der Sluis, Warrier and Ophoff22,Reference Baltramonaityte, Pingault, Cecil, Choudhary, Järvelin and Penninx23} We established addiction-related, cognitive and socioeconomic traits as mediators (Fig. 3). The direct effect of childhood maltreatment persisted, particularly for MDD. Epigenetic Mendelian randomisation revealed ten childhood maltreatment-associated CpG sites associated with outcomes, highlighting novel pathways for further investigation.

Fig. 3 Breakdown of the mediators of the relationship between childhood maltreatment (CM) and neuropsychiatric disorders, potential mechanisms and suggested interventions. Mediators in red are addiction-related traits, mediators in green are cognitive-related traits and the mediator in blue is a socioeconomic trait. Solid arrows represent causal links and the dashed arrow represents associations, not causality. DNAm, DNA methylation; ADHD, attention-deficit/hyperactivity disorder; MDD, major depressive disorder; OR, odds ratio.

Interpretation of our findings and comparison with the literature

Our results support the associations between childhood maltreatment and mediators reported in observational studies. Childhood maltreatment was reported to reduce cognitive functioning, intelligence ^{Reference Matte-Landry, Grisé Bolduc, Tanguay-Garneau, Collin-Vézina and Ouellet-Morin45} and academic achievement, ^{Reference Fry, Fang, Elliott, Casey, Zheng and Li46} and to increase tobacco and illicit drug use. ^{Reference Petruccelli, Davis and Berman8} The magnitude of these differed slightly compared with our Mendelian randomisation estimates. Genetic instruments used in Mendelian randomisation studies affect the usual levels of exposure over long periods of time, corresponding to a lifetime effect of the exposure. ^{Reference Burgess, Davey Smith, Davies, Dudbridge, Gill and Glymour38} For example, educational attainment in observational studies has larger effect sizes compared with our Mendelian randomisation estimates. This may reflect childhood maltreatment impact during short yet sensitive periods, when brain development is highly susceptible to external stimuli. However, childhood maltreatment occurs during sensitive periods in childhood development, specifically when brain development is highly susceptible to external stimuli. ^{Reference Schaefer, Cheng and Dunn47} This could explain the larger effects on educational outcomes in observational studies as compared with our Mendelian randomisation estimates. Nevertheless, the directionality of our results was consistent with observational associations, validating our findings.

The results in step two of mediation Mendelian randomisation align with literature that has reported a significant causal effect of executive functioning, educational attainment and smoking initiation on ADHD, MDD and schizophrenia. ^{Reference Ahn, Norman, Justice and Shaw48–Reference Treur, Demontis, Smith, Sallis, Richardson and Wiers51}

In applying novel Mendelian randomisation methods to delineate mediators, we validated hypothesised mechanisms linking childhood maltreatment and outcomes. Previous studies delineated childhood maltreatment as a predictor of reduced executive functioning, ^{Reference Letkiewicz, Funkhouser and Shankman52,Reference Masson, Bussières, East-Richard, R-Mercier and Cellard53} and Mendelian randomisation studies showed that this increased the risks of ADHD, MDD and schizophrenia. ^{Reference Ahn, Norman, Justice and Shaw48,Reference Burton, Sallis, Hatoum, Munafò and Reed49} We add to this by establishing temporal ordering between childhood maltreatment, executive functioning and neuropsychiatric outcomes. Early life stressors impair executive functioning through atypical development of brain regions including the prefrontal cortex, which influences emotional regulation and reward processing. ^{Reference Kasai, Koike, Matsuoka, Okada, Sakakibara and Sakurada54} Reduced educational attainment exacerbates these cognitive deficits. ^{Reference Fry, Fang, Elliott, Casey, Zheng and Li46,Reference Masson, Bussières, East-Richard, R-Mercier and Cellard53,Reference Puetz and McCrory55} These mechanisms contribute to reduced stress tolerance and the inability to disengage from rumination, resulting in increased risk of adult neuropsychiatric disorders. ^{Reference Rock, Roiser, Riedel and Blackwell56}

In observational studies, childhood maltreatment was reported to lower educational attainment. ^{Reference Fry, Fang, Elliott, Casey, Zheng and Li46,Reference Romano, Babchishin and Marquis57} Adding to this, we found that educational attainment mediated the effect of childhood maltreatment on ADHD and MDD. At the individual level, exposure to childhood maltreatment impacts brain and cognitive development, causing mental health problems. ^{Reference Fry, Fang, Elliott, Casey, Zheng and Li46} Challenges associated with mental health further limit educational attainment and, consequently, cognitive impairments persist. At a social level, childhood maltreatment-exposed children are neither provided with social and emotional support nor exposed to environments fostering a sense of agency or self-efficacy. ^{Reference Romano, Babchishin and Marquis57,Reference Slade and Wissow58} As such, they are unable to internalise the value of education, leading to poorer educational outcomes. These suggest that educational, child welfare and care-giving sectors contribute to sustaining limited educational attainment and increased risk of neuropsychiatric outcomes. ^{Reference Romano, Babchishin and Marquis57}

Although smoking and alcohol dependency were commonly reported as consequences of childhood maltreatment, ^{Reference Petruccelli, Davis and Berman8} our analyses supported only smoking initiation and substance abuse as mediators of the relationship between childhood maltreatment and ADHD. Non-significant indirect effects of other smoking traits may be due to limited power from smaller sample sizes. Alternatively, the self-medication hypothesis states that victims who experienced trauma use illicit substances as a coping mechanism to reduce awareness and maintain a dissociated state. ^{Reference Schimmenti, Billieux, Santoro, Casale and Starcevic59} Thus, without healthy coping mechanisms, these behaviours can elicit unexpected effects – for example, reducing the risk of neuropsychiatric disorders. ^{Reference Brady, Phalen, Roche, Cowan and Bennett60}

We formally delineated novel mediators such as leisure screen time and risk tolerance. The role of risk tolerance can be explained by impaired cognitive functioning, whereas leisure screen time is more complex. Leisure screen time may be a form of avoidant coping hindering emotional regulation development. ^{Reference Westerlund, Alvarsson, Carli and Hadlaczky61} However, its effect on outcomes remains uncertain due to the wide content variety and influences on coping strategies. ^{Reference Westerlund, Alvarsson, Carli and Hadlaczky61,Reference Tang, Werner-Seidler, Torok, Mackinnon and Christensen62} Therefore, further research into the implication of leisure screen time as a mediator is required.

Another novelty of our study is the application of epigenetic Mendelian randomisation to establish outcome-specific DNAm signatures. Significant CpG sites were near genes responsible for biological pathways such as apoptosis (HNRNPK, CLU, RPTOR) and transcription regulation (H2BC6, HNRNPK).

Pathway analysis of these mapped genes identified a functionally enriched in neurofibrillary tangle formation pathways, involving CLU, MAPT and HNRNPK. Neurofibrillary tangles are a hallmark of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, acting as a precursor to microtubule destabilisation and dysregulated dynamics of the neuronal skeleton. ^{Reference Metaxas and Kempf63} Our results showed that hypomethylation at the MAPT gene, corresponding to increased expression of the tau protein, was associated with increased schizophrenia risk. ^{Reference Coupland, Mellick, Silburn, Mather, Armstrong and Sachdev64} HNRNPK, an RNA protein, influences the development of early tau pathology, ^{Reference Kavanagh, Halder and Drummond65} and CLU (clusterin) binds and stabilises tau to prevent degradation, thereby accelerating tau aggregation and its neurotoxic properties. ^{Reference Yuste-Checa, Trinkaus, Riera-Tur, Imamoglu, Schaller and Wang66} Interestingly, increased tau levels were previously associated with depression, anxiety and ADHD. ^{Reference Hall, Petersen and Johnson67,Reference Demirci68} Contrastingly, both total and phosphorylated tau levels were lower in patients with schizophrenia. ^{Reference Demirel, Cetin, Turan, Yıldız, Sağlam and Duran69} Nevertheless, tau pathology has a potential mechanistic role in the pathogenesis of neuropsychiatric disorders. We further identified one additional signal at the RPTOR (regulatory associated protein of MTOR complex 1) gene, which is part of the mTORC1 pathway. This stress-related pathway is reported to be downregulated in the prefrontal cortex of humans and rats with schizophrenia. ^{Reference Chen, Guan, Wang and Lin70,Reference Sanacora, Yan and Popoli71} This aligns with our results, which show that childhood maltreatment-induced hypomethylation at RPTOR, triggering the MTORC1 pathway, was associated with increased schizophrenia risk. Considering the two key findings from our epigenetic Mendelian randomisation analysis, we hypothesise that early childhood adversities such as childhood maltreatment are linked to neuropsychiatric outcomes, possibly through changes in DNAm at key genes involved in neurobiological and/or stress pathways.

However, these epigenetic Mendelian randomisation results should be interpreted with caution. First, the full GWAS summary statistics for DNAm at each CpG site were not available, precluding formal two-step epigenetic mediation Mendelian randomisation analyses and delineation of CpG sites as true causal mediators. Nevertheless, the specificity of genetic instruments ensured specificity of the DNAm effect and allowed postulation of biological mechanisms. Significant CpG sites were near genes responsible for biological pathways such as apoptosis (HNRNPK, CLU, RPTOR) and transcription regulation (H2BC6, HNRNPK). Second, DNAm levels were proxied by at most three mQTLs, which explains only a small proportion of the variation in DNAm. This may overlook any true causal associations resulting from larger methylation changes that are not captured by the selected mQTLs. Third, we considered DNAm levels only in whole blood, potentially missing DNAm signatures in other relevant tissues, including the brain. Nevertheless, we considered all CpG sites associated with any adverse childhood exposures in a hypothesis-free approach to identify potential novel epigenetic mediators. We recognise that epigenetic Mendelian randomisation alone is insufficient to establish biological mechanisms. Therefore, these findings warrant further research to confirm the biological role of each gene in the pathogenesis of ADHD, MDD and schizophrenia in victims. This may identify new markers to screen for high-risk victims, or novel therapeutic targets to reduce the risk of neuropsychiatric disorders.

Clinical implications

Despite SDG Target 16.2 aiming to end abuse against children by 2030, ^{Reference Lee and Kim4,Reference Clark, Coll-Seck, Banerjee, Peterson, Dalglish and Ameratunga72} a large proportion of the adult population is expected to have a history of childhood maltreatment following the COVID-19 pandemic. The direct effect on neuropsychiatric outcomes is indisputable, and therefore strengthening care-giving and economic support for high-risk families would prevent childhood maltreatment by creating a safe environment. ^{Reference Malvaso, Pilkington, Montgomerie, Delfabbro and Lynch73} The consequences of childhood maltreatment can be mitigated through early detection and intervention. Screening for childhood maltreatment history in clinical settings may be an effective strategy to identify high-risk individuals for adverse neuropsychiatric outcomes. ⁷⁴ Through this, timely provision of trauma-informed therapy and increased access to community trauma services can prevent further childhood maltreatment and mitigate negative consequences.

Addiction-related, cognitive and socioeconomic mediators may be interdependent. For example, without healthy coping strategies, successful prevention of addiction in the childhood maltreatment victim may lead them to engage in other unhealthy behaviours. Therefore, policies and interventions need to target the multidimensional consequences of childhood maltreatment. Simultaneous addiction prevention and provision of psychoeducation and skills to cope with trauma was proposed as an effective intervention. ^{Reference Bailey, Newton, Perry, Grummitt, Baams and Barrett75} ‘Rise Above’ is an example of an evidence-based trauma-informed prevention programme. This is a comprehensive intervention curriculum for youths covering trauma, education on e-cigarette and drug use, psychosocio-emotional development and prosocial behaviour. ^{Reference Shin76} In providing the necessary coping tools for childhood maltreatment victims, the detrimental impacts on mental health can be mitigated. Moreover, psychotherapies, including trauma-focused cognitive behavioural therapy, facilitate the development of cognitive coping strategies to improve self-regulation, while cognitive remediation focuses on strategies that improves cognitive functioning. ^{Reference Masson, Bussières, East-Richard, R-Mercier and Cellard53,Reference Rhoades, Mitnick, Heyman, Slep, Del Vecchio, Wampler and McWey77} Furthermore, close coordination between educational, child welfare and care-giving sectors is required to enable access to education, and to foster a positive attitude towards education in childhood maltreatment victims. ^{Reference Romano, Babchishin and Marquis57} Therefore, a holistic approach is required to reach the therapeutic potential of trauma-informed interventions.

Strengths and limitations

This study used mediation and epigenetic Mendelian randomisation to provide novel insight into the pathways between childhood maltreatment and neuropsychiatric outcomes. It overcomes the limitations of unmeasured confounding and reverse causation in traditional observational study designs to delineate key causal mediators, effectively prioritising areas for intervention.

Our findings should be taken in the context of several limitations. First, while the Mendelian randomisation framework generates causal evidence, one must satisfy the Mendelian randomisation assumptions. Nevertheless, sensitivity analyses and instrument strength were satisfactory for UVMR analyses, and MVMR analyses accounting for weak instruments showed unlikely biased results. Second, childhood maltreatment and some mediators were based on self-reported measurements. Incorrect group assignment or reporting bias in the original study may have biased our results. Third, childhood maltreatment was reported as a composite measure of childhood maltreatment subtypes. We could not evaluate the effects of childhood maltreatment subtypes on outcomes. Fourth, the direct and indirect effects of binary mediators may be inaccurate given the non-collapsibility of odds ratios. However, a recent study showed that log(odds ratio) could be used as an outcome unit to calculate indirect effects. ^{Reference Carter, Sanderson, Hammerton, Richmond, Davey Smith and Heron16} Fifth, our analyses were limited by the type and availability of data. GWAS data-sets used in Mendelian randomisation analyses were limited to European ancestry, and caution is required when generalising these findings to other populations. As discussed, formal mediation epigenetic Mendelian randomisation analyses were not possible with the current data. Furthermore, mQTLs were also limited to regions within 1 Mb from the CpG site, resulting in very few instruments to proxy DNAm levels. Although this may have limited instrument strength, the specificity of genetic instruments enabled postulation of biological mechanisms. Sixth, the effect sizes presented in this study represent a lifetime average effect of exposures on outcomes. Thus, mediators with large effects acting within shorter time frames may have been overlooked in this study. Finally, the heritability of childhood maltreatment is moderate, and genetic instruments represent gene–environmental interactions such as transgenerational transmission and passive or evocative heritability. ^{Reference Espinosa Dice, Lawn, Ratanatharathorn, Roberts, Denckla and Kim78} Because genetics are more stable and predictable than environmental factors, our findings are based on childhood maltreatment variance, as determined by the myriad of childhood maltreatment risk factors with which the variants are associated. ^{Reference ter Kuile, Hübel, Cheesman, Coleman, Peel and Levey79} While the genetic and environmental causes of childhood maltreatment are not distinguished, our findings determine the consequences of childhood maltreatment regardless of the underlying cause. Such analyses reflect how childhood maltreatment is perpetrated, and present crucial evidence to guide interventions.

In conclusion, our results support the role of addiction-related, cognitive and socioeconomic traits in mediating the effect of childhood maltreatment on neuropsychiatric disorders. Responsive interventions in these areas may be more relevant for ADHD and schizophrenia, but not for MDD. These include addiction prevention and treatment, improving cognitive functioning and supporting socioeconomic attainment. Ultimately, preventative strategies are vital to reducing childhood maltreatment prevalence and its long-term impacts. ^{Reference Ng80}