Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder.

Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, which we call a pharmagenic enrichment score (PES), identify individuals with a higher burden of genetic risk, localized in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

Patterns of health service use for children with mental disorders in an Australian state population cohort.

OBJECTIVES: The rate of mental health services provided to children and young people is increasing worldwide, including in Australia. The aim of this study was to describe patterns of hospital and ambulatory mental health service use among a large population cohort of adolescents followed from birth, with consideration of variation by age, sex and diagnosis. METHODS: Characteristics of services provided for children with mental disorder diagnoses between birth and age 17.5 years were ascertained for a population cohort of 85,642 children (52.0% male) born between 2002 and 2005, from 'Admitted Patients', 'Emergency Department' and 'Mental Health Ambulatory' records provided by the New South Wales and Australian Capital Territory Health Departments. RESULTS: A total of 11,205 (~13.1%) children received at least one hospital or ambulatory health occasion of service for a mental health condition in the observation period. More than two-fifths of children with mental disorders had diagnoses spanning multiple categories of disorder over time. Ambulatory services were the most heavily used and the most common point of first contact. The rate of mental health service contact increased with age across all services, and for most categories of mental disorder. Girls were more likely to receive services for mental disorders than boys, but boys generally had an earlier age of first service contact. Finally, 3.1% of children presenting to mental health services experienced involuntary psychiatric inpatient admission. CONCLUSIONS: The extent of hospital and ambulatory-based mental healthcare service among children emphasises the need for primary prevention and early intervention.

Early life exposure to air pollution and psychotic-like experiences, emotional symptoms, and conduct problems in middle childhood.

BACKGROUND: Air pollution has been linked to a variety of childhood mental health problems, but results are inconsistent across studies and the effect of exposure timing is unclear. We examined the associations between air pollution exposure at two time-points in early development and psychotic-like experiences (PLEs), and emotional and conduct symptoms, assessed in middle childhood (mean age 11.5 years). METHODS: Participants were 19,932 children selected from the NSW Child Development Study (NSW-CDS) with available linked multi-agency data from birth, and self-reported psychotic-like experiences (PLEs) and psychopathology at age 11-12 years (middle childhood). We used binomial logistic regression to examine associations between exposure to nitrogen dioxide (NO2) and particulate matter less than 2.5 µm (PM2.5) at two time-points (birth and middle childhood) and middle childhood PLEs, and emotional and conduct symptoms, with consideration of socioeconomic status and other potential confounding factors in adjusted models. RESULTS: In fully adjusted models, NO2 exposure in middle childhood was associated with concurrent PLEs (OR = 1.10, 95% CI = 1.02-1.20). Similar associations with PLEs were found for middle childhood exposure to PM2.5 (OR = 1.05, 95% CI = 1.01-1.09). Neither NO2 nor PM2.5 exposure was associated with emotional symptoms or conduct problems in this study. CONCLUSIONS: This study highlights the need for a better understanding of potential mechanisms of action of NO2 in the brain during childhood.

Cumulative environmental risk in early life is associated with mental disorders in childhood.

BACKGROUND: No single environmental factor is a necessary or sufficient cause of mental disorder; multifactorial and transdiagnostic approaches are needed to understand the impact of the environment on the development of mental disorders across the life course. METHOD: Using linked multi-agency administrative data for 71 932 children from the New South Wales Child Developmental Study, using logistic regression, we examined associations between 16 environmental risk factors in early life (prenatal period to <6 years of age) and later diagnoses of mental disorder recorded in health service data (from age 6 to 13 years), both individually and summed as an environmental risk score (ERS). RESULTS: The ERS was associated with all types of mental disorder diagnoses in a dose-response fashion, such that 2.8% of children with no exposure to any of the environmental factors (ERS = 0), compared to 18.3% of children with an ERS of 8 or more indicating exposure to 8 or more environmental factors (ERS ⩾ 8), had been diagnosed with any type of mental disorder up to age 13-14 years. Thirteen of the 16 environmental factors measured (including prenatal factors, neighbourhood characteristics and more proximal experiences of trauma or neglect) were positively associated with at least one category of mental disorder. CONCLUSION: Exposure to cumulative environmental risk factors in early life is associated with an increased likelihood of presenting to health services in childhood for any kind of mental disorder. In many instances, these factors are preventable or capable of mitigation by appropriate public policy settings.

Early childhood developmental vulnerability associated with parental mental disorder comorbidity.

OBJECTIVES: Parental mental health has a profound influence on the mental health and well-being of their offspring. With comorbid mental disorders generally the rule rather than the exception, increased knowledge of the impact of parental mental disorder comorbidity on early child development may facilitate improved targeting and delivery of early intervention for vulnerable offspring. METHODS: Participants were 66,154 children and their parents in the New South Wales Child Development Study - a prospective, longitudinal, record-linkage study of a population cohort of children born in NSW between 2002 and 2004. Early childhood developmental vulnerability was assessed at age ~5 years using the Australian Early Development Census, and information on parental mental disorders was obtained from administrative health records. Binomial and multinomial logistic regression were used to assess the relationship between parental mental disorders and early childhood developmental vulnerability on emotional and behavioural domains, as well as membership of latent developmental risk classes reflecting particular classes of vulnerability. RESULTS: Multiple diagnoses of mental disorders in mothers and fathers were associated with an increased likelihood of early childhood emotional and behavioural developmental vulnerability in offspring, relative to parents without mental disorder. The likelihood of offspring vulnerability increased with the number of parental comorbidities, particularly maternal comorbidities. CONCLUSION: Early childhood developmental vulnerability was strongly associated with parental mental ill-health, with the strength of associations increasing in line with a greater number of mental disorder diagnoses among mothers and fathers. New and expectant parents diagnosed with multiple mental disorders should be prioritised for intervention, including attention to the developmental well-being of their offspring.

Self-harm and suicidal ideation among young people is more often recorded by child protection than health services in an Australian population cohort.

OBJECTIVE: We investigated patterns of service contact for self-harm and suicidal ideation recorded by a range of human service agencies - including health, police and child protection - with specific focus on overlap and sequences of contacts, age of first contact and demographic and intergenerational characteristics associated with different service responses to self-harm. METHODS: Participants were 91,597 adolescents for whom multi-agency linked data were available in a longitudinal study of a population cohort in New South Wales, Australia. Self-harm and suicide-related incidents from birth to 18 years of age were derived from emergency department, inpatient hospital admission, mental health ambulatory, child protection and police administrative records. Descriptive statistics and binomial logistic regression were used to examine patterns of service contacts. RESULTS: Child protection services recorded the largest proportion of youth with reported self-harm and suicidal ideation, in which the age of first contact for self-harm was younger relative to other incidents of self-harm recorded by other agencies. Nearly 40% of youth with a health service contact for self-harm also had contact with child protection and/or police services for self-harm. Girls were more likely to access health services for self-harm than boys, but not child protection or police services. CONCLUSION: Suicide prevention is not solely the responsibility of health services; police and child protection services also respond to a significant proportion of self-harm and suicide-related incidents. High rates of overlap among different services responding to self-harm suggest the need for cross-agency strategies to prevent suicide in young people.

Parental mental disorders and offspring schizotypy in middle childhood: an intergenerational record linkage study.

PURPOSE: To investigate relationships between distinct schizotypy risk profiles in childhood and the full spectrum of parental mental disorders. METHODS: Participants were 22,137 children drawn from the New South Wales Child Development Study, for whom profiles of risk for schizophrenia-spectrum disorders in middle childhood (age ~ 11 years) were derived in a previous study. A series of multinomial logistic regression analyses examined the likelihood of child membership in one of three schizotypy profiles (true schizotypy, introverted schizotypy, and affective schizotypy) relative to the children showing no risk, according to maternal and paternal diagnoses of seven types of mental disorders. RESULTS: All types of parental mental disorders were associated with membership in all childhood schizotypy profiles. Children in the true schizotypy group were more than twice as likely as children in the no risk group to have a parent with any type of mental disorder (unadjusted odds ratio [OR] = 2.27, 95% confidence intervals [CI] = 2.01-2.56); those in the affective (OR = 1.54, 95% CI = 1.42-1.67) and introverted schizotypy profiles (OR = 1.39, 95% CI = 1.29-1.51) were also more likely to have been exposed to any parental mental disorder, relative to children showing no risk. CONCLUSION: Childhood schizotypy risk profiles appear not to be related specifically to familial liability for schizophrenia-spectrum disorders; this is consistent with a model where liability for psychopathology is largely general rather than specific to particular diagnostic categories.

Pathways from developmental vulnerabilities in early childhood to schizotypy in middle childhood.

OBJECTIVES: Childhood disturbances in social, emotional, language, motor and cognitive functioning, and schizotypy have each been implicated as precursors of schizophrenia-spectrum disorders. We investigated whether relationships between early childhood developmental vulnerabilities and childhood schizotypy are mediated by educational underachievement in middle childhood. METHODS: Participants were members of a large Australian (n = 19,216) population cohort followed longitudinally. Path analyses were used to model relationships between developmental vulnerabilities at age ~5 years, educational underachievement from ages ~8 to 10 years and three distinct profiles of schizotypy at age ~11 years (true, introverted and affective schizotypy). RESULTS: Early childhood developmental vulnerabilities on five broad domains (related to physical, emotional, social, cognitive and communication development) were associated with schizotypy profiles in middle childhood. Educational underachievement in middle childhood was associated with all schizotypy profiles, but most strongly with the true schizotypy profile (OR = 3.92, 95% CI = 3.12, 4.91). The relationships between schizotypy profiles and early childhood developmental vulnerabilities in 'language and cognitive skills (school-based)' and 'communication skills and general knowledge' domains were fully mediated by educational underachievement in middle childhood, and the relationships with early childhood 'physical health and well-being' and 'emotional maturity' domains were partially mediated. CONCLUSION: Developmental continuity from early childhood developmental vulnerabilities to schizotypy in middle childhood is mediated by educational underachievement in middle childhood. While some domains of early developmental functioning showed differential relationships with distinct schizotypy profiles, these findings support a developmental pathway to schizotypy in which cognitive vulnerability operates from early childhood through to middle childhood.

Profiles of Resilience from Early to Middle Childhood among Children Known to Child Protection Services.

OBJECTIVE: The processes facilitating resilience are likely to be influenced by individual, familial and contextual factors that are dynamic across the life-course. These factors have been less studied in relation to resilience profiles evident in the developmental period between early to middle childhood, relative to later periods of adolescence or adulthood. METHOD: This study examined factors associated with resilience in a cohort of 4,716 children known to child protection services by age 13 years, in the Australian State of New South Wales. Latent profile and transition analyses were used to identify multi-dimensional profiles of resilience as evident in social, emotional and cognitive functioning when assessed in early childhood (time 1 [T1], age 5-6 years) and middle childhood (time 2 [T2], age 10-11 years). Logistic regression models were used to investigate factors associated with two types of resilience identified: a transition profile of stress-resistance (i.e., represented by a typically developing profile at both T1 and T2) delineated in the largest subgroup (54%) of children, and a smaller subgroup (13%) with a profile of emergent resilience (i.e., typically developing at T2 following a vulnerable profile at T1). RESULTS: Factors associated with resilience profiles included being female, and personality characteristics of openness and extraversion; other factors associated with stress-resistance, specifically, included higher socioeconomic status, non-Indigenous background, higher perceived port at home and at school, and not having a parent with a history of criminal offending. CONCLUSIONS: Resilience processes appear to involve a complex interplay between individual, family, and community characteristics requiring interagency support.

Self-reported mental health of children known to child protection services: an Australian population-based record linkage study.

Maltreated children are vulnerable to adverse mental health outcomes. Information about how children's mental health needs vary according to different levels of child protection contact (potentially culminating in out-of-home care [OOHC]) is valuable for the effective provision of services. This study aimed to examine associations between different levels of contact with child protection services before the age of 10 years and self-reported mental health difficulties at age 11 years. Participants (n = 26,960) were drawn from the New South Wales Child Development Study, a multiagency, multigenerational, longitudinal record linkage study that combines administrative records with cross-sectional survey data. We examined associations between four levels of child protection response (non-threshold reports, unsubstantiated reports, substantiated reports, OOHC; each relative to no report) and six domains of self-reported mental health difficulties (including internalising and externalising symptoms, and psychotic-like experiences). All levels of contact with child protection services were associated with increased odds of mental health difficulties in all domains. Children who had been placed in OOHC and children with substantiated reports had the highest odds of reporting clinical levels of mental health difficulties; 48.1% of children with an OOHC placement and 45.6% of those with substantiated child protection reports showed clinical levels of mental health difficulties in at least one domain. Children with child protection reports that were unsubstantiated, or determined not to meet the threshold for risk-of-significant harm, were also at increased risk of mental health difficulties in middle childhood. These findings underscore the importance of early detection and intervention for all children at risk of maltreatment.

Cumulative comorbidity between neurodevelopmental, internalising, and externalising disorders in childhood: a network approach.

Cumulative comorbidity of mental disorders is common, but the extent and patterns of comorbid psychopathology in childhood are not well established. The current study aimed to elucidate the emergent patterns of cumulative mental disorder comorbidity in children using network analysis of diagnoses recorded between birth and age 12 years. Participants were 90,269 children (mean age 12.7 years; 51.8% male) within the New South Wales Child Development Study (NSW-CDS)-a longitudinal record-linkage cohort study of Australian children born in NSW between 2002 and 2005. Binary indicators for eight types of mental disorder were derived from administrative health records. Patterns of conditional association between mental disorders were assessed utilising network analysis. Of 90,269 children, 2268 (2.5%) had at least one mental disorder by age 12 years; of the 2268 children who had at least one mental disorder by age 12 years, 461 (20.3%) were diagnosed with two or more different disorders out of the eight disorder types included in analyses. All disorders were either directly or indirectly interconnected, with childhood affective and emotional disorders and developmental disorders being most central to the network overall. Mental disorder nodes aggregated weakly (modularity = 0.185) into two communities, representative of internalising and externalising disorders, and neurodevelopmental and sleep disorders. Considerable sex differences in the structure of the mental disorder comorbidity networks were also observed. Developmental and childhood affective and emotional disorders appear to be key to mental disorder comorbidity in childhood, potentially reflecting that these disorders share symptoms in common with many other disorders.

Conditions of Birth and Early Childhood Developmental Risk for Mental Disorders.

Distinct classes of children in the general population are at increased odds of later mental illness and other adverse outcomes according to patterns of early childhood developmental vulnerability. If certain risk factors known at the time of birth are reliably associated with membership in early childhood risk classes, then preventative interventions could be initiated in the earliest years of life. Associations between 14 factors known at the time of birth and membership in early childhood risk classes were examined in 66,464 children. Risk class membership was associated with maternal mental illness, parental criminal charges and being male; distinct patterns of association were shown for some conditions, for example, prenatal child protection notification was uniquely associated with misconduct risk'. These findings suggest that risk factors known at the time of birth could assist in very early detection of children who may benefit from early intervention in the first 2000 days.

Relationships between parental mental illness and/or offending and offspring contact with the police in childhood: Findings from a longitudinal record-linkage study.

BACKGROUND: Parental offending and mental illness are associated with an increased risk of criminal behaviour in offspring during adolescence and adulthood, but the impact of such problems on younger children, including children's experiences of victimisation, is less well known. AIM: To investigate the associations between parental offending and mental illness recorded prior to their offspring's age of 5 years and their offspring's contact with police as a 'person of interest', 'victim' or 'witness' between ages 5 and 13 years. METHODS: Our sample consisted of 72,771 children and their parents drawn from the New South Wales Child Development Study, an Australian longitudinal population-based record linkage study. Logistic regression analyses were conducted to examine associations between parental factors and offspring's police contact. Separate models examined the relationships between maternal or paternal offending and mental illness, as well as the combination among either or both parents, as the independent variables, and their child's police contact as the dependent variable. RESULTS: Parental offending and mental illness were each individually associated with indices of police contact among offspring. Stronger associations were observed when both offending and mental illness were present together (in either parent, or when one parent had both exposures). Stronger associations were evident for mothers with both factors across all offspring police contact types, relative to fathers with both factors, in fully adjusted models; that is, children of mothers with both factors were over four times as likely to have contact with police as a 'person of interest' (OR = 4.29; 95% CI = 3.75-4.92) and over three times as likely to have contact as a victim (OR = 3.35; 95% CI = 3.01-3.74) or witness (OR = 3.58; 95% CI = 3.03-4.24), than children whose mothers had no history of offending or mental illness. CONCLUSIONS: Children with a parental history of offending and mental illness in early life are at an increased likelihood of early police contact as young as 5-13 years of age; it is vital that this is taken as a signal to help them and their affected families according to need.

Forecasting childhood adversities from conditions of birth.

BACKGROUND: Childbirth presents an optimal time for identifying high-risk families to commence intervention that could avert various childhood health and social adversities. OBJECTIVE: We sought to establish the minimum set of exposures required to accurately predict a range of adverse childhood outcomes up to the age of 13 years, from a set of 14 individual and familial risk exposures evident at the time of birth. METHODS: Participants were 72,059 Australian children and their parents drawn from a multi-register population cohort study (data spanning 1994-2018). Risk exposures included male sex, young mother (aged ≤21 years), no (or late first; >16 weeks) antenatal visit, maternal smoking during pregnancy, small for gestational age, preterm birth, pregnancy complications (any of hypertension, diabetes mellitus, gestational diabetes or pre-eclampsia), >2 previous pregnancies of ≥20 weeks, socio-economic disadvantage, prenatal child protection notification, and maternal or paternal mental disorder or criminal offending history. Individual outcomes included early childhood developmental vulnerability (age 5 years), sustained educational underachievement (age 8 and 10 years), mental disorder diagnoses, substantiated childhood maltreatment, and contact with the police as a victim or person-of-interest up to age 13-14 years. RESULTS: Risk exposures at birth predicted individual childhood outcomes with fair to excellent accuracy: the area under the receiver operating characteristic curves ranged between 0.60 (95% CI 0.58, 0.62) for childhood mental disorder and 0.83 (95% CI 0.82, 0.85) for substantiated child maltreatment. The presence of five or more exposures characterised 12-25% of children with one or more adverse outcomes and showed high predictive certainty for models predicting multiple outcomes, which were apparent in 9% of the population. CONCLUSIONS: Up to a quarter of the neonatal population at risk of multiple adverse outcomes can be detected at birth, with implications for population health screening. However, cautious implementation of these models is warranted, given their relatively low positive predictive values.

Interactive effects of polygenic risk and cognitive subtype on brain morphology in schizophrenia spectrum and bipolar disorders.

Grey matter volume (GMV) may be associated with polygenic risk for schizophrenia (PRS-SZ) and severe cognitive deficits in people with schizophrenia, schizoaffective disorder (collectively SSD), and bipolar disorder (BD). This study examined the interactive effects of PRS-SZ and cognitive subtypes of SSD and BD in relation to GMV. Two-step cluster analysis was performed on 146 clinical cases (69 SSD and 77 BD) assessed on eight cognitive domains (verbal and visual memory, executive function, processing speed, visual processing, language ability, working memory, and planning). Among them, 55 BD, 51 SSD, and 58 healthy controls (HC), contributed to focal analyses of the relationships between cognitive subtypes, PRS-SZ and their interaction on GMV. Two distinct cognitive subtypes were evident among the combined sample of cases: a 'cognitive deficit' group (CD; N = 31, 20SSD/11BD) showed severe impairment across all cognitive indices, and a 'cognitively spared' (CS; N = 75; 31SSD/44BD) group showed intermediate cognitive performance that was significantly worse than the HC group but better than the CD subgroup. A cognitive subgroup-by-PRS-SZ interaction was significantly associated with GMV in the left precentral gyrus. Moderation analyses revealed a significant negative relationship between PRS-SZ and GMV in the CD group only. At low and average (but not high) PRS-SZ, larger precentral GMV was evident in the CD group compared to both CS and HC groups, and in the CS group compared to HCs. This study provides evidence for a relationship between regional GMV changes and PRS-SZ in psychosis spectrum cases with cognitive deficits, but not in cases cognitively spared.

Health-related quality of life in people with psychotic disorders: The role of loneliness and its contributors.

BACKGROUND: Perception of loneliness has been identified as the strongest predictor of health-related quality of life assessed with the Assessment of Quality of Life-4D in people with psychotic disorders. We aimed to establish contributors to perceived loneliness, and ascertain the mediating role of loneliness in the relationship between identified contributors to loneliness and other known predictors of health-related quality of life with health-related quality of life. METHODS: Data for 1642 people collected as part of the 2010 Australian National Survey of Psychosis were analysed. Health-related quality of life was assessed using the Assessment of Quality of Life-4D, and loneliness through a single-item five-level categorical variable. To identify independent contributors to loneliness, a statistical model was constructed with reference to a theoretical model comprising 23 variables. A predictive model with health-related quality of life as the dependent variable was then developed and tested to assess the mediating role of loneliness. RESULTS: Nine contributors to loneliness were found (social dysfunction, experienced stigma, contact with friends, diagnosis, depressive symptoms, anxiety, mental health service utilisation, arthritis and traumatic events in childhood), with social dysfunction the strongest. In the prediction of health-related quality of life, all contributors to loneliness were partially mediated through loneliness (except service utilisation) as were negative symptoms and use of psychotropic/anticholinergic medications. CONCLUSION: Assuming a plausible causal model of mediation, loneliness was found to have direct and indirect effects on health-related quality of life in people with psychotic disorders. Findings add impetus to efforts to develop and trial strategies aimed at reducing loneliness in this population, and, in turn, improving their health-related quality of life.

Developmental profiles of schizotypy in the general population: A record linkage study of Australian children aged 11-12 years.

OBJECTIVES: The detection of young people at high risk for psychotic disorders has been somewhat narrowly focused on overt symptom-based markers that reflect mild reality distortion (e.g., psychotic-like experiences), or prodromal syndromes that are proximal to psychosis onset. The concept of schizotypy represents a broader framework for investigating risk for schizophrenia (and other disorders) in childhood, before the onset of prodromal or overt symptoms. We sought to detect profiles of risk for psychosis (schizotypy) in a general population sample of 22,137 Australian children aged 11-12 years, and to determine early life risk factors associated with these profiles from data available in linked records (registers). METHODS: Fifty-nine self-reported items were used as indicators of schizotypy across six broad domains; z-scores for each domain were subjected to latent profile analyses (LPA). A series of multinomial logistic regressions was used to examine the association between resulting profile (class) membership and several childhood and parental risk factors, and the proportion of children with mental disorders among each schizotypy profile was examined. RESULTS: The LPA revealed three person-centred profiles referred to as True Schizotypy (n = 1,323; 6.0%), Introverted Schizotypy (n = 4,473; 20.2%), and Affective Schizotypy (n = 4,261; 19.2%), as well as a group of children showing no risk (n = 12,080; 54.6%). Prior exposure to perinatal and familial adversities including childhood maltreatment, as well as poor early childhood development and academic functioning, was variously associated with all risk groups. There was a higher proportion of childhood mental disorder diagnoses among children in the True Schizotypy group, relative to other profiles. CONCLUSION: Subtle differences in the pattern of exposures and antecedents among schizophrenia liability profiles in childhood may reflect distinct pathogenic pathways to psychotic or other mental illness. PRACTITIONER POINTS: Children aged 11-12 years report characteristics of schizotypy which can be classified into three distinct profiles that may represent different pathological processes towards later mental ill-health. Early life exposure to perinatal and familial adversities including childhood maltreatment, early childhood developmental vulnerability, and poor academic functioning predict membership in all three childhood schizotypy profiles. Latent liability for schizophrenia (and potentially other mental disorders) may be represented by different profiles of functioning observable in childhood.

Increased incidence of childhood mental disorders following exposure to early life infection.

Early life exposure to infectious diseases confers risk for adult psychiatric disorders but relatively few human population studies have examined associations with childhood mental disorder. Here we examined the effects of exposure to maternal infection during pregnancy, and child infectious diseases in early childhood (birth to age 4 years), in relation to first mental disorder diagnosis (age 5-13 years). The study sample comprised 71,841 children represented in a population cohort of children in New South Wales, Australia, followed from birth to early adolescence via linkage of administrative registers. Childhood exposure to infectious disease was determined during the prenatal period (i.e., maternal infection during gestation), and in early childhood (between birth and age 4 years) using the NSW Ministry of Health Admitted Patients data collection. Days to first diagnosis with a mental disorder was determined from recorded diagnoses between age 5-13 years in the NSW Ministry of Health's Admitted Patients, Emergency Department and Mental Health Ambulatory data collections. While crude hazard ratios for both prenatal infection and childhood infection exposures indicated significantly earlier diagnosis with mental disorders associated with both of these risk factors, only childhood infection exposure was associated with higher adjusted hazard ratios (aHR) for any diagnoses (aHR = 1.21, 95% CI = 1.11-1.32), externalising disorders (aHR = 1.45, 95% CI 1.18-1.79) and developmental disorders (aHR = 1.82, 95% CI 1.49-2.22) when the effects of maternal and early childhood (age < 5 years) mental disorders were taken into account. Exposure to infectious diseases during early childhood, but not prenatal infection exposure, appears to be associated with earlier diagnosis of mental disorders in childhood.

Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype.

Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRSRet) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRSRet to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRSRet, were enriched with rare variation in the retinoic acid receptor beta gene RARB, detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.