Childhood abuse v. neglect and risk for major psychiatric disorders.

BACKGROUND: Childhood maltreatment (CM) is a strong risk factor for psychiatric disorders but serves in its current definitions as an umbrella for various fundamentally different childhood experiences. As first step toward a more refined analysis of the impact of CM, our objective is to revisit the relation of abuse and neglect, major subtypes of CM, with symptoms across disorders. METHODS: Three longitudinal studies of major depressive disorder (MDD, N = 1240), bipolar disorder (BD, N = 1339), and schizophrenia (SCZ, N = 577), each including controls (N = 881), were analyzed. Multivariate regression models were used to examine the relation between exposure to abuse, neglect, or their combination to the odds for MDD, BD, SCZ, and symptoms across disorders. Bidirectional Mendelian randomization (MR) was used to probe causality, using genetic instruments of abuse and neglect derived from UK Biobank data (N = 143 473). RESULTS: Abuse was the stronger risk factor for SCZ (OR 3.51, 95% CI 2.17-5.67) and neglect for BD (OR 2.69, 95% CI 2.09-3.46). Combined CM was related to increased risk exceeding additive effects of abuse and neglect for MDD (RERI = 1.4) and BD (RERI = 1.1). Across disorders, abuse was associated with hallucinations (OR 2.16, 95% CI 1.55-3.01) and suicide attempts (OR 2.16, 95% CI 1.55-3.01) whereas neglect was associated with agitation (OR 1.24, 95% CI 1.02-1.51) and reduced need for sleep (OR 1.64, 95% CI 1.08-2.48). MR analyses were consistent with a bidirectional causal effect of abuse with SCZ (IVWforward = 0.13, 95% CI 0.01-0.24). CONCLUSIONS: Childhood abuse and neglect are associated with different risks to psychiatric symptoms and disorders. Unraveling the origin of these differences may advance understanding of disease etiology and ultimately facilitate development of improved personalized treatment strategies.

Differences in Parenting Behavior are Systematic Sources of the Non-shared Environment for Internalizing and Externalizing Problem Behavior.

Although there is evidence for non-shared environmental links between parenting and problem behavior, so far, age-, informant-, and parent-specific patterns for both internalizing and externalizing problem behaviors have not been examined within one study yet. Using the twin differences design, the present study aimed to test how maternal and paternal parenting systematically act as a source of non-shared environment for problem behavior across different age groups and informants. We examined 1327 monozygotic twin pairs and their parents drawn from three birth cohorts of the German TwinLife study. Our results revealed that particularly child-reported less positive and more negative parenting by both parents contribute significantly to the unique environmental variance of problem behavior, although we did not find a clear pattern across age groups. Our study underlines the necessity of controlling for genetic confounding to uncover the truly environmentally mediated (and thus environmentally influenceable) pathways between parenting and problem behavior. A practical implication could be that it may be useful to primarily consider the child's perspective and focus on maternal as well as paternal parenting in interventions that address parenting to reduce problem behavior.

Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways.

BACKGROUND: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth. METHODS: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers. RESULTS: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms. CONCLUSIONS: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

Annual Research Review: Towards a deeper understanding of nature and nurture: combining family-based quasi-experimental methods with genomic data.

Distinguishing between the effects of nature and nurture constitutes a major research goal for those interested in understanding human development. It is known, for example, that many parent traits predict mental health outcomes in children, but the causal processes underlying such associations are often unclear. Family-based quasi-experimental designs such as sibling comparison, adoption and extended family studies have been used for decades to distinguish the genetic transmission of risk from the environmental effects family members potentially have on one another. Recently, these designs have been combined with genomic data, and this combination is fuelling a range of exciting methodological advances. In this review we explore these advances - highlighting the ways in which they have been applied to date and considering what they are likely to teach us in the coming years about the aetiology and intergenerational transmission of psychopathology.

If we build it, will they come? Commentary on "Preventing eating disorders and disordered eating in high-risk families".

Levine and Sadeh-Sharvit (2023) open the door to a logical and evidence-based targeted prevention strategy adapted from the field of depression. Their proposal is likely to benefit parents who are dealing with their own eating disorders and disordered eating while simultaneously breaking the cycle of risk inherent in the intergenerational transmission of eating disorders. The approach honors the wishes of parents who desperately want to buffer their children from the pain they experienced with their own suffering and provides hope for reducing environmental exposures that could augment any genetic risk that children of affected parents may hold.

Comparing Within- and Between-Family Polygenic Score Prediction.

Polygenic scores are a popular tool for prediction of complex traits. However, prediction estimates in samples of unrelated participants can include effects of population stratification, assortative mating, and environmentally mediated parental genetic effects, a form of genotype-environment correlation (rGE). Comparing genome-wide polygenic score (GPS) predictions in unrelated individuals with predictions between siblings in a within-family design is a powerful approach to identify these different sources of prediction. Here, we compared within- to between-family GPS predictions of eight outcomes (anthropometric, cognitive, personality, and health) for eight corresponding GPSs. The outcomes were assessed in up to 2,366 dizygotic (DZ) twin pairs from the Twins Early Development Study from age 12 to age 21. To account for family clustering, we used mixed-effects modeling, simultaneously estimating within- and between-family effects for target- and cross-trait GPS prediction of the outcomes. There were three main findings: (1) DZ twin GPS differences predicted DZ differences in height, BMI, intelligence, educational achievement, and ADHD symptoms; (2) target and cross-trait analyses indicated that GPS prediction estimates for cognitive traits (intelligence and educational achievement) were on average 60% greater between families than within families, but this was not the case for non-cognitive traits; and (3) much of this within- and between-family difference for cognitive traits disappeared after controlling for family socio-economic status (SES), suggesting that SES is a major source of between-family prediction through rGE mechanisms. These results provide insights into the patterns by which rGE contributes to GPS prediction, while ruling out confounding due to population stratification and assortative mating.

Association between genetic and socioenvironmental risk for schizophrenia during upbringing in a UK longitudinal cohort.

BACKGROUND: Associations of socioenvironmental features like urbanicity and neighborhood deprivation with psychosis are well-established. An enduring question, however, is whether these associations are causal. Genetic confounding could occur due to downward mobility of individuals at high genetic risk for psychiatric problems into disadvantaged environments. METHODS: We examined correlations of five indices of genetic risk [polygenic risk scores (PRS) for schizophrenia and depression, maternal psychotic symptoms, family psychiatric history, and zygosity-based latent genetic risk] with multiple area-, neighborhood-, and family-level risks during upbringing. Data were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins born in 1994-1995 and followed to age 18 (93% retention). Socioenvironmental risks included urbanicity, air pollution, neighborhood deprivation, neighborhood crime, neighborhood disorder, social cohesion, residential mobility, family poverty, and a cumulative environmental risk scale. At age 18, participants were privately interviewed about psychotic experiences. RESULTS: Higher genetic risk on all indices was associated with riskier environments during upbringing. For example, participants with higher schizophrenia PRS (OR = 1.19, 95% CI = 1.06-1.33), depression PRS (OR = 1.20, 95% CI = 1.08-1.34), family history (OR = 1.25, 95% CI = 1.11-1.40), and latent genetic risk (OR = 1.21, 95% CI = 1.07-1.38) had accumulated more socioenvironmental risks for schizophrenia by age 18. However, associations between socioenvironmental risks and psychotic experiences mostly remained significant after covariate adjustment for genetic risk. CONCLUSION: Genetic risk is correlated with socioenvironmental risk for schizophrenia during upbringing, but the associations between socioenvironmental risk and adolescent psychotic experiences appear, at present, to exist above and beyond this gene-environment correlation.

Genetic Risk for Smoking: Disentangling Interplay Between Genes and Socioeconomic Status.

This study aims to disentangle the contribution of genetic liability, educational attainment (EA), and their overlap and interaction in lifetime smoking. We conducted genome-wide association studies (GWASs) in UK Biobank (N = 394,718) to (i) capture variants for lifetime smoking, (ii) variants for EA, and (iii) variants that contribute to lifetime smoking independently from EA ('smoking-without-EA'). Based on the GWASs, three polygenic scores (PGSs) were created for individuals from the Netherlands Twin Register (NTR, N = 17,805) and the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2, N = 3090). We tested gene-environment (G × E) interactions between each PGS, neighborhood socioeconomic status (SES) and EA on lifetime smoking. To assess if the PGS effects were specific to smoking or had broader implications, we repeated the analyses with measures of mental health. After subtracting EA effects from the smoking GWAS, the SNP-based heritability decreased from 9.2 to 7.2%. The genetic correlation between smoking and SES characteristics was reduced, whereas overlap with smoking traits was less affected by subtracting EA. The PGSs for smoking, EA, and smoking-without-EA all predicted smoking. For mental health, only the PGS for EA was a reliable predictor. There were suggestions for G × E for some relationships, but there were no clear patterns per PGS type. This study showed that the genetic architecture of smoking has an EA component in addition to other, possibly more direct components. PGSs based on EA and smoking-without-EA had distinct predictive profiles. This study shows how disentangling different models of genetic liability and interplay can contribute to our understanding of the etiology of smoking.

Commentary: Will genomics revolutionise research on gene-environment interplay?

The synthesis of quantitative genetics and molecular genetics is transforming research in the behavioural sciences. The ability to measure inherited DNA differences directly has led to polygenic scores and to new methods to estimate heritability and genetic correlations. This issue provides examples of how these advances can be appllied to research on gene-environment interplay in developmental psychopathology.

On the importance of parenting in externalizing disorders: an evaluation of indirect genetic effects in families.

BACKGROUND: Theoretical models of the development of childhood externalizing disorders emphasize the role of parents. Empirical studies have not been able to identify specific aspects of parental behaviors explaining a considerable proportion of the observed individual differences in externalizing problems. The problem is complicated by the contribution of genetic factors to externalizing problems, as parents provide both genes and environments to their children. We studied the joint contributions of direct genetic effects of children and the indirect genetic effects of parents through the environment on externalizing problems. METHODS: The study used genome-wide single nucleotide polymorphism data from 9,675 parent-offspring trios participating in the Norwegian Mother Father and child cohort study. Based on genomic relatedness matrices, we estimated the contribution of direct genetic effects and indirect maternal and paternal genetic effects on ADHD, conduct and disruptive behaviors at 8 years of age. RESULTS: Models including indirect parental genetic effects were preferred for the ADHD symptoms of inattention and hyperactivity, and conduct problems, but not oppositional defiant behaviors. Direct genetic effects accounted for 11% to 24% of the variance, whereas indirect parental genetic effects accounted for 0% to 16% in ADHD symptoms and conduct problems. The correlation between direct and indirect genetic effects, or gene-environment correlations, decreased the variance with 16% and 13% for conduct and inattention problems, and increased the variance with 6% for hyperactivity problems. CONCLUSIONS: This study provides empirical support to the notion that parents have a significant role in the development of childhood externalizing behaviors. The parental contribution to decrease in variation of inattention and conduct problems by gene-environment correlations would limit the number of children reaching clinical ranges in symptoms. Not accounting for indirect parental genetic effects can lead to both positive and negative bias when identifying genetic variants for childhood externalizing behaviors.

Genotype-environment correlation by intervention effects underlying middle childhood peer rejection and associations with adolescent marijuana use.

Aggressive behavior in middle childhood can contribute to peer rejection, subsequently increasing risk for substance use in adolescence. However, the quality of peer relationships a child experiences can be associated with his or her genetic predisposition, a genotype-environment correlation (rGE). In addition, recent evidence indicates that psychosocial preventive interventions can buffer genetic predispositions for negative behavior. The current study examined associations between polygenic risk for aggression, aggressive behavior, and peer rejection from 8.5 to 10.5 years, and the subsequent influence of peer rejection on marijuana use in adolescence (n = 515; 256 control, 259 intervention). Associations were examined separately in control and intervention groups for children of families who participated in a randomized controlled trial of the family-based preventive intervention, the Family Check-Up . Using time-varying effect modeling (TVEM), polygenic risk for aggression was associated with peer rejection from approximately age 8.50 to 9.50 in the control group but no associations were present in the intervention group. Subsequent analyses showed peer rejection mediated the association between polygenic risk for aggression and adolescent marijuana use in the control group. The role of rGEs in middle childhood peer processes and implications for preventive intervention programs for adolescent substance use are discussed.

Gene-environment interplays between family chaos and emotional problems among Nigerian adolescents: A twin study.

Gene-environment correlations and interactions for the relationship between emotional problems (EP) and family environment in adolescents in low- to middle-income countries (LMIC) have been rarely investigated. In total, 3207 adolescent twins aged 12-18 (Mean = 14.6 ± 1.73) years attending public schools in Lagos State in Nigeria completed measures of EP and Family Chaos (FC). Model-fitting analyses suggested that genetic and non-shared environmental influences on EP were 21% and 71%, respectively, and the corresponding estimates were 23% and 71% for FC. Shared environmental influences were not significant (8% and 6% respectively). Phenotypic correlation between EP and FC was .30 (95% CI = .27-.34), which was significantly influenced by genetic (A - 49%, 95% CI: 0.01-0.97) and non-shared environmental factors (E - 32%, 95% CI: 0.10-0.54). Shared environmental influences were not significant (C - 19%, 95% CI: -0.13 to 0.50). Moderation effects were significant whereby as FC increased, A on EP decreased (ßA = -0.07, 95% CI: -0.12 to -0.02) while E increased (ßE = 0.06, 95% CI: 0.03-0.09). Our findings indicate that genetic and non-shared environmental risk factors may mediate the relationship between EP and FC, and that as FC increases, protective genetic influences on EP may be attenuated, whereas environmental influences may become stronger in adolescents in LMIC.

The role of parental genotype in the intergenerational transmission of externalizing behavior: Evidence for genetic nurturance.

The purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents' own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children's externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent-child communication, less parent-child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children's environmental experiences, and the role of children's genotypes in shaping parent-child relationships.

Challenging the utility of polygenic scores for social science: Environmental confounding, downward causation, and unknown biology.

The sociogenomics revolution is upon us, we are told. Whether revolutionary or not, sociogenomics is poised to flourish given the ease of incorporating polygenic scores (or PGSs) as "genetic propensities" for complex traits into social science research. Pointing to evidence of ubiquitous heritability and the accessibility of genetic data, scholars have argued that social scientists not only have an opportunity but a duty to add PGSs to social science research. Social science research that ignores genetics is, some proponents argue, at best partial and likely scientifically flawed, misleading, and wasteful. Here, I challenge arguments about the value of genetics for social science and with it the claimed necessity of incorporating PGSs into social science models as measures of genetic influences. In so doing, I discuss the impracticability of distinguishing genetic influences from environmental influences because of non-causal gene-environment correlations, especially population stratification, familial confounding, and downward causation. I explain how environmental effects masquerade as genetic influences in PGSs, which undermines their raison d'être as measures of genetic propensity, especially for complex socially contingent behaviors that are the subject of sociogenomics. Additionally, I draw attention to the partial, unknown biology, while highlighting the persistence of an implicit, unavoidable reductionist genes versus environments approach. Leaving sociopolitical and ethical concerns aside, I argue that the potential scientific rewards of adding PGSs to social science are few and greatly overstated and the scientific costs, which include obscuring structural disadvantages and cultural influences, outweigh these meager benefits for most social science applications.

Disentangling nature from nurture in examining the interplay between parent-child relationships, ADHD, and early academic attainment.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is highly heritable and is associated with lower educational attainment. ADHD is linked to family adversity, including hostile parenting. Questions remain regarding the role of genetic and environmental factors underlying processes through which ADHD symptoms develop and influence academic attainment. METHOD: This study employed a parent-offspring adoption design (N = 345) to examine the interplay between genetic susceptibility to child attention problems (birth mother ADHD symptoms) and adoptive parent (mother and father) hostility on child lower academic outcomes, via child ADHD symptoms. Questionnaires assessed birth mother ADHD symptoms, adoptive parent (mother and father) hostility to child, early child impulsivity/activation, and child ADHD symptoms. The Woodcock-Johnson test was used to examine child reading and math aptitude. RESULTS: Building on a previous study (Harold et al., 2013, Journal of Child Psychology and Psychiatry, 54(10), 1038-1046), heritable influences were found: birth mother ADHD symptoms predicted child impulsivity/activation. In turn, child impulsivity/activation (4.5 years) evoked maternal and paternal hostility, which was associated with children's ADHD continuity (6 years). Both maternal and paternal hostility (4.5 years) contributed to impairments in math but not reading (7 years), via impacts on ADHD symptoms (6 years). CONCLUSION: Findings highlight the importance of early child behavior dysregulation evoking parent hostility in both mothers and fathers, with maternal and paternal hostility contributing to the continuation of ADHD symptoms and lower levels of later math ability. Early interventions may be important for the promotion of child math skills in those with ADHD symptoms, especially where children have high levels of early behavior dysregulation.

Genetic liability to schizophrenia is associated with exposure to traumatic events in childhood.

BACKGROUND: There is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene-environment correlation. METHODS: The association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0-17 years; ALSPAC) and at age 8 years (MoBa). RESULTS: Within ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable with those of MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure. CONCLUSIONS: Results from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. Genome-wide association study of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.

Direct and Indirect Effects of Maternal, Paternal, and Offspring Genotypes: Trio-GCTA.

Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to three exemplar phenotypes: offspring birth weight, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).

No Evidence for Passive Gene-Environment Correlation or the Influence of Genetic Risk for Psychiatric Disorders on Adult Body Composition via the Adoption Design.

The relationship between genetic and environmental risk is complex and for many traits, estimates of genetic effects may be inflated by passive gene-environment correlation. This arises because biological offspring inherit both their genotypes and rearing environment from their parents. We tested for passive gene-environment correlation in adult body composition traits using the 'natural experiment' of childhood adoption, which removes passive gene-environment correlation within families. Specifically, we compared 6165 adoptees with propensity score matched non-adoptees in the UK Biobank. We also tested whether passive gene-environment correlation inflates the association between psychiatric genetic risk and body composition. We found no evidence for inflation of heritability or polygenic scores in non-adoptees compared to adoptees for a range of body composition traits. Furthermore, polygenic risk scores for anorexia nervosa, attention-deficit/hyperactivity disorder and schizophrenia did not differ in their influence on body composition traits in adoptees and non-adoptees. These findings suggest that passive gene-environment correlation does not inflate genetic effects for body composition, or the influence of psychiatric disorder genetic risk on body composition. Our design does not look at passive gene-environment correlation in childhood, and does not test for 'pure' environmental effects or the effects of active and evocative gene-environment correlations, where child genetics directly influences home environment. However, these findings suggest that genetic influences identified for body composition in this adult sample are direct, and not confounded by the family environment provided by biological relatives.

The role of child negative emotionality in parenting and child adjustment: Gene-environment interplay.

BACKGROUND: Evocative gene-environment correlation (rGE) describes a process through which children's heritable characteristics influence their rearing environments. The current study examined whether heritable influences on parenting and children's behavioural outcomes operate through child negative emotionality. METHOD: Using data from the Early Growth and Development Study, we examined associations among adoptive parent reports of child anger and sadness at 4.5 years, adoptive parents' hostile and warm parenting at 6 years and child behavioural problems and social competence at age 7. Birth parent temperament was included to test whether child effects on parents reflect evocative gene-environment correlation (rGE). RESULTS: Child anger at 4.5 years evoked hostile parenting from adoptive parents at 6 years, which was subsequently related to child problem behaviours at 7 years. Evocative rGE effects were identified for adoptive parents' hostile parenting. CONCLUSIONS: By employing a genetically informed design, we found that birth parent temperament was related to child negative emotionality. Adoptive parents were sensitive to child negative emotionality, and this sensitivity was linked to the child's later adjustment.

Childhood adversity and psychosis: a systematic review of bio-psycho-social mediators and moderators.

The association between childhood adversity (CA) and psychosis has been extensively investigated in recent years. An increasing body of research has also focused on the mediating or moderating role of biological and psychological mechanisms, as well as other risk factors that might account for the link between CA and psychosis. We conducted a systematic search of the PsychINFO, Embase, Ovid, and Web of Science databases for original articles investigating the role of genetic vulnerabilities, environmental factors, psychological and psychopathological mechanisms in the association between CA and psychosis up to August 2019. We included studies with individuals at different stages of the psychosis continuum, from subclinical psychotic experiences to diagnosed disorders. From the 28 944 records identified, a total of 121 studies were included in this review. Only 26% of the studies identified met the criteria for methodological robustness. Overall, the current evidence suggests that CA may be associated with psychosis largely independently of genetic vulnerabilities. More consistent and robust evidence supports interaction between early and recent adversities, as well as the mediating role of attachment and mood symptoms, which is suggestive of an affective pathway between CA and psychosis across the continuum from subclinical experiences to diagnosable disorder. This review highlighted numerous methodological issues with the existing literature, including selection bias, heterogeneity of measurement instruments utilised, and lack of control for potential confounders. Future research should address these limitations to more accurately estimate mediation and moderation effects on the CA-psychosis association to inform the development of preventive interventions.