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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.

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from t

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functio

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.

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.

There is known to be considerable overlap among the victims and perpetrators of crime. However, the extent of this overlap early in life among children and young adolescents is not clear. We examined the sociodemographic profiles of young people who had early contact with police regarding a criminal incident as a person of interest, victim and/or witness, as well as the patterns of multiple police contact types from birth to 13 years of age. Data were drawn from a longitudinal, population-based sample of 91,631 young people from New South Wales, Australia. Among the 10.6% (n = 9677) of young people who had contact with police, 14.4% (n = 1393) had contact as a person of interest and as a victim and/or witness on two or more separate occasions. The most common first contact type was as a victim/witness, but those children with a first contact as a person of interest were most likely to have at least one further contact. Young people with both types of police contact were younger at first police contact, were more likely to reside in a socioeconomically disadvantaged area, and to be recorded as having an Aboriginal and/or Torres Strait Islander background. Our findings demonstrate that, by 13 years of age, 1 in 10 young people had been in early contact with police and that a minority have contact with the police as both a person of interest and a victim/witness. These young people may represent a particularly disadvantaged group in the community who are likely to be at risk of future adversity, including repeated contact with the criminal justice system.

Children with disabilities are known to have high rates of contact with child protection services. However, little is known about child protection contacts for a broader group of children with special healthcare needs (SHCN; i.e., special needs or other impairments of concern that affect learning). This study examined the characteristics of contact with child protection services (prior to the age of 6 years) for children with SHCN identified at school entry using the 2009 Australian Early Development Census, using administrative data from more than 65,000 children in the New South Wales Child Development Study. Child protection contacts prior to age 6 years were more prevalent among children with SHCN compared with those without; in particular, children with SHCN had higher odds of a history of exposure to neglect and physical abuse, and higher odds of being placed in out-of-home care, compared with their typically developing peers. Understanding the characteristics of child protection contacts among children with SHCN, with consideration of factors that may influence their patterns of contact with these and other human services agencies, will inform the development of appropriate social policy initiatives to fulfil Australia’s obligations under the United Nations Convention on the Rights of the Child.

Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA's expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

Background: Elevated levels of systemic inflammation are consistently reported in both schizophrenia (SZ) and bipolar-I disorder (BD), and are associated with childhood trauma exposure. We tested whether childhood trauma exposure moderates associations between systemic inflammation and brain morphology in people with these diagnoses. Methods: Participants were 55 SZ cases, 52 BD cases and 59 healthy controls (HC) who underwent magnetic resonance imaging. Systemic inflammation was measured using a composite z-score derived from serum concentrations of interleukin 6, tumor necrosis factor alpha and C-reactive protein. Indices of grey matter volume covariation (GMC) were derived from independent component analysis. Childhood trauma was measured using the Childhood Trauma Questionnaire (CTQ Total score). Results: A series of moderated moderation analyses indicated that increased systemic inflammation were associated with increased GMC in the striatum and cerebellum among all participants. Severity of childhood trauma exposure moderated the relationship between systemic inflammation and GMC in one component, differently among the groups. Specifically, decreased GMC in the PCC/precuneus, parietal lobule and postcentral gyrus, and increased GMC in the left middle temporal gyrus was associated with increased systemic inflammation in HC individuals exposed to high (but not low or average) levels of trauma and in SZ cases exposed to low (but not average or high) levels of trauma, but not in BD cases. Conclusions: Increased systemic inflammation is associated with grey matter changes in people with psychosis, and these relationships may be partially and differentially moderated by childhood trauma exposure according to diagnosis.

Parental history of offending and/or mental illness are risk factors for child maltreatment. However, limited research has directly contrasted the role of maternal versus paternal criminal offending or mental health problems in contributing to earlier contact with the child protection system. In this study we examined the relative contributions of these risk factors in relation to the time to the offspring’s first report to child protection services, or first placement in out of home care (OOHC), using administrative records for a population sample of 71,661 children. Prior paternal offending had a greater independent effect on time to the offspring’s first contact with child protection services (HR = 2.27 [95% CI = 2.14-2.40]) than maternal offending (HR = 1.75 [95% CI = 1.63 -1.87]) or maternal mental disorder diagnosis (HR = 1.66 [95% CI = 1.57 -1.77]). By contrast, prior maternal offending (HR = 2.58 [95% CI = 2.26-2.95]) and mental disorder diagnosis (HR = 2.33 [95% CI = 2.05-2.63]) had a greater effect on earlier placement in OOHC, relative to prior paternal offending (HR = 1.59 [95% CI = 1.35 -1.88]) and mental disorder diagnosis (HR = 1.06 [95% CI = 0.94 -1.19]). These findings demonstrate the potential benefits of coordinated government responses across multiple agencies to identify vulnerable children and families who might benefit from early interventions or support services.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

This study aimed to establish independent predictors for health-related quality of life (HRQoL) in people with psychotic disorders, and the mediating role of global functioning in those relationships. Data for 1642 people collected as part of the second Australian National Survey of Psychosis were analyzed. The Assessment of Quality of Life (AQoL)-4D and the Personal and Social Performance scale were used for assessing HRQoL and global functioning respectively. The study commenced with a theoretical model comprised of 26 sociodemographic and clinical variables. A predictive model for HRQoL was built up using a purposeful selection strategy to arrive at a set of clinically meaningful, independent predictors. The mediating effect of global functioning was then assessed. Seven variables were found to have an independent effect on HRQoL: perception of loneliness, number of negative symptoms, use of psychotropic and anticholinergic medications, course of disorder, lifetime histories of chronic pain and cardiovascular disease and living arrangements at the time of the interview. All variables except perceived loneliness and chronic pain were partially mediated through global functioning. This final model explained 46% of the variance in HRQoL, with loneliness and number of negative symptoms the strongest predictors. Evidence in support of a credible causal pathway for HRQoL in people with psychotic disorders, mediated by global functioning was presented. The importance of the quality of social relationships was highlighted, and potential targets for improving the HRQoL of this population identified.

Childhood trauma is a risk factor for psychotic and mood disorders that is associated with abnormal hypothalamic–pituitary–adrenal (HPA) axis function in response to stress and abnormal social brain function. Here, we aimed to determine whether childhood trauma exposure would differently moderate associations between cortisol reactivity and social brain function, among cases with schizophrenia (SZ), bipolar disorder (BD) and in healthy individuals (HC). Forty cases with SZ, 35 with BD and 34 HCs underwent functional magnetic resonance imaging while performing an emotional face-matching task. Participants completed the Childhood Trauma Questionnaire and cortisol reactivity (i.e. the slope indexing the within-subject difference between pre- and post-imaging salivary cortisol levels) was determined. The severity of childhood trauma moderated the relationship between cortisol reactivity and brain activation in the bilateral temporo-parieto-insular junctions, right middle cingulum, right pre/postcentral gyri, left cerebellum and right lingual gyrus, differently depending on the clinical group. When exposed to high levels of trauma, the cortisol slope was negatively associated with activation in these regions in HC, while the cortisol slope was positively associated with activation in these regions in SZ cases. Similarly, there were differences between the groups in how trauma severity moderated the relationship between cortisol reactivity and functional connectivity between the amygdala and dorsolateral prefrontal cortex. In addition to reflecting typical associations between cortisol reactivity and emotional brain function when not exposed to childhood trauma, these findings provide new evidence that trauma exposure disrupts these relationships in both healthy individuals and in cases with SZ or BD.

Adult psychosocial difficulties, including psychiatric disorders, are often preceded by childhood psychosocial vulnerabilities, presenting critical windows of opportunity for preventative intervention. The present study aimed to identify longitudinal patterns (representing transitions between profiles) of childhood socio-emotional and cognitive vulnerability in the general population from early to middle childhood, in relation to key risk factors (e.g. parental mental illness and offending). Data were drawn from the New South Wales Child Development Study, which combines intergenerational multi-agency administrative records with cross-sectional assessments using data linkage methods. We analysed data from childhood assessments of socio-emotional and cognitive functioning at two time points (ages 5–6 and 10–11 years) that were linked with administrative data from government departments of health, child protection, and education for 19,087 children and their parents. Latent profile analyses were used to identify socio-emotional and cognitive profiles at each time point, and latent transition analyses were used to determine the probability and potential moderators of transition between profiles at each age. Three developmental profiles were identified in early childhood, reflecting typically developing, emotionally vulnerable, and cognitively vulnerable children, respectively; two profiles were identified in middle childhood, reflecting typically developing and vulnerable children. Child’s sex, child protection services contact, parental mental illness, and parental offending influenced children’s transitions between different vulnerability profiles, with the strongest effects for parental mental illness and child protection contact. Early detection of vulnerable children and factors promoting resilience are important steps in directing future health and social policy, and service planning for vulnerable children.

Objectives: To examine associations between being the subject of child protection reports in early childhood and diagnoses of mental disorders during middle childhood, by level of service response. Design, setting, participants: Retrospective analysis of linked New South Wales administrative data, 2001–2016, for a population cohort of children (mean age in 2016, 13.2 years; SD, 0.37 years) enrolled in the longitudinal NSW Child Development Study (NSW-CDS), wave 2 linkage. Main outcome measures: Associations between being the subject of a child protection report (any, and by level of child protection response) during early childhood (birth to 6 years of age) and diagnoses of mental disorders during middle childhood (6–14 years). Results: 13 796 of 74 462 children in the NSW-CDS (18.5%) had been the subjects of reports to child protection services during early childhood: 1148 children had been placed in out-of-home care at least once, and 1680 had been the subjects of substantiated risk-of-significant-harm reports but were not placed in care, while 9161 had non-substantiated reports, and 1807 had reports of facts that did not reach the threshold for significant harm. After adjusting for sex, socio-economic disadvantage, perinatal complications, and parental mental illness, early childhood contact with protection services was associated with increased frequency of being diagnosed with a mental disorder during middle childhood (adjusted odds ratio [aOR], 2.72; 95% CI, 2.51–2.95). The frequency was highest for children who had been placed in out-of-home care (aOR, 5.25; 95% CI, 4.46–6.18). Conclusion: Childhood-onset mental disorders are more frequently diagnosed in children who come to the attention of child protection services during early childhood, particularly in children placed in out-of-home care.

Background: Longitudinal data on health costs associated with physical and mental conditions are not available for children reported to child protection services. Objective: To estimate the costs of hospitalization for physical and mental health conditions by child protection status, including out-of-home-care (OOHC) placement, from birth until 13-years, and to assess the excess costs associated with child protection contact over this period. Participants and setting: Australian population cohort of 79,285 children in a multi-agency linkage study. Methods: Costs of hospitalization were estimated from birth (if available) using Round 17, National Hospital Cost Data Collection (2012-13; deflated to 2015-16 AUD). Records of the state child protection authority determined contact status. Data were reported separately for children in OOHC. Hospital separations were classified as mental disorder-related if the primary diagnosis was recorded in ICD-10 Chapter V (F00-F99). Results: Hospital separations were more common in children with child protection contact. Physical health care costs per child decreased with age for all children, but were significantly higher for children with contact. Mental health costs per child were always significantly higher for children with contact, with marked increases at 3 ≤ 4 years and 8 ≤ 9 years. Point estimates of annual costs per child were always highest for children with an OOHC placement. The net present value of the excess costs was $3,224 per child until 13- years, discounted at 5 %. Conclusions: Children in contact with child protection services show higher rates and costs for physical and mental health hospitalizations in each of their first 13 years of life.

Background: Maltreated children are at risk of poor educational outcomes, but also experience greater individual, family, and neighbourhood adversities that may obscure an understanding of relationships between child protection involvement and educational attainment. Objective: To examine associations between child protection involvement and 3rd- and 5th-grade reading and numeracy attainment, while controlling multiple other adversities. Participants and Setting: Participants were 56,860 Australian children and their parents from the New South Wales Child Development Study with linked multi-agency records. Methods: Multinomial logistic regressions examined associations between level of child protection involvement (Out-Of-Home Care [OOHC] placement; substantiated Risk Of Significant Harm [ROSH]; unsubstantiated ROSH; non-ROSH; and no child protection report) and standardised tests of 3rd- and 5th-grade reading and numeracy. Fully adjusted models controlled demographic, pregnancy, birth, and parental factors, and early (kindergarten) developmental vulnerabilities on literacy and numeracy, and other developmental domains (social, emotional, physical, communication). Results: All children with child protection reports were more likely to attain below average, and less likely to attain above average, 3rd- and 5th-grade reading and numeracy, including children with reports below the ROSH threshold. Children with substantiated ROSH reports who were not removed into care demonstrated the worst educational attainment, with some evidence of protective effects for children in OOHC. Conclusions: A cross-agency response to supporting educational attainment for all children reported to child protection services is required, including targeted services for children in OOHC or with substantiated ROSH reports, and referral of vulnerable families (unsubstantiated and non-ROSH cases) to secondary service organisations (intermediate intervention).

Objectives: Childhood psychotic-like experiences (PLEs) increase risk for concurrent and future psychiatric disorders but are common in the population. Strategies are needed to identify vulnerable individuals who may benefit from monitoring or targeted intervention. This study aimed to delineate profiles of childhood PLEs that might be differentially associated with other psychopathologies, and multiple psychopathology. Design: Cross-sectional, online self-report survey. Methods: Participants were 27,000 Australian children from a population cohort (13,416 girls; mean age 11.91 years) who completed an online self-report questionnaire assessing PLEs (hallucinations and delusions) and Emotional, Peer Relationship, Conduct, and Hyperactivity–Inattention psychopathology. Latent class analysis differentiated classes of children showing different patterns of PLE responses, and multinomial logistic regression determined the association between the PLE classes and the various psychopathologies, adjusted for demographic covariates and the other psychopathologies. Results: Five latent profiles of PLE responses were characterized as follows: None (27.4% of children), Minor (29.7%), Moderate (11.8%), Hallucinatory (21.0%), and Strong (10.2%). These classes showed distinct associations with other psychopathologies (odds ratios between 1.27 and 4.58), and dose–response relationships indicated increasing likelihood of multiple psychopathology for the Hallucinatory and Strong classes (odds ratio = 21.87 for ≥3 psychopathologies in the Strong class). Conclusions: Tailored interventions that address the particular needs of these different classes of individuals may be warranted. Practitioner points: Children aged 11–12 years who report psychotic-like experiences (PLEs) can be classified into five different PLE profiles based on self-reported questionnaire responses, which may reflect different pathological processes. These PLE profiles show different patterns and magnitudes of increa

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.

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.

Contact with the police, as the first contact with the criminal justice system for young people and children, may signify individuals who are vulnerable to later adverse social and health outcomes. However, little is known about how often children have contact with police or for what reason. In this paper, we provide a demographic profile of the prevalence and reasons for police contact among a representative, longitudinal, population-based sample of 91,631 young people in New South Wales, Australia. By 13 years of age, almost one in six (15.6%) children had contact with police as a victim, person of interest and/or witness on at least one occasion. The most common reason for contact with police was in relation to an assault. There was considerable overlap among children who had been in contact with police on more than one occasion for different reasons, with those having police contact as a person of interest or witness being seven times more likely to have also been in contact with police as a victim in a separate incident, than children not known to police. We show that contact with the police is surprisingly common among children and suggest that early interventions for children in contact with police might prevent a range of adverse outcomes not limited to criminal offending.

Prior investigations indicate that the five core personality dimensions (the “Big Five”) are measurable by middle childhood. The aim of this research was to examine the psychometric properties of a short-form self-report measure of the Big Five personality dimensions in children that would be suitable for administration online in large population-based studies. Twen-ty-five questionnaire items in English, derived from the 65-item Big Five Questionnaire for Children in Italian (Barbaranelli, Caprara, Rabasca, & Pastorelli, 2003), were completed online by 27,415 Australian children in Year 6 (mean age 11.92 years). An item response theory approach evaluated the psychometric properties and resolved a 20-item short-form questionnaire. Exploratory and confirmatory factor analyses supported the Big Five structure. Construct validity was demonstrated via correlations between Big Five scores and the Strengths and Difficulties Questionnaire subscales (Goodman, 2001). The 20 items provide a brief, reliable, and valid child self-report measure of the Big Five personality dimensions.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

To inform development of a model for health-related quality of life (HRQoL) in people with psychotic disorders, we aimed to assess correlations between utilities and dimension scores for the Assessment of Quality of Life (AQoL)-4D with functioning and social experiences; ascertain if patient housing and clinical status affected correlations; and determine aspects of functioning that jointly predict HRQoL. We analyzed data for 1642 people with an ICD-10 psychotic disorder from the 2010 Australian National Survey of Psychosis. Global functioning was measured with the Personal and Social Performance scale, independent functioning with the Multidimensional Scale of Independent Functioning and social functioning through level of social dysfunction. Social experiences comprised perceived loneliness and experienced stigma. We assessed Spearman’s rank correlation coefficients and undertook linear regression analyses. Moderate associations were found between AQoL-4D utilities and all variables, except experienced stigma. Perceived loneliness had the strongest association. The AQoL-4D social relationships dimension was most strongly associated with social variables; its independent living dimension with global and independent functioning. Correlations between utilities and all variables, except for social dysfunction, were modified by housing. Course of disorder impacted correlations with utilities and independent functioning. Global functioning and social dysfunction were found to jointly predict HRQoL. In conclusion, as the AQoL-4D can differentiate between functioning and social experiences individually and when categorized by housing and clinical status in people with psychosis, predictive models of HRQoL in this population are feasible, and only need include select aspects of functioning and social experiences, particularly perception of loneliness.

Objective This study examined associations between chronic physical health conditions (identified from hospital records) that are subject to school health care plans, and children’s emotional, behavioral, and social functioning during early (~5 years of age) and middle childhood (~11 years). Methods Participants were 21,304 Australian children from a representative longitudinal population cohort derived by multi-agency record linkage. Hospital presentations (admitted patients and emergency department) identified children with asthma (n = 1,573), allergies and anaphylaxis (n = 738), type 1 diabetes (n = 59), epilepsy (n = 87), and any of these conditions (n = 2,275), relative to 19,029 children without these presentations. Logistic regression analyses determined associations between these exposures and (i) emotional, behavioral, social, and overall vulnerabilities reported by teachers (early childhood) and children (middle childhood), and (ii) self-reported lack of sources of support (middle childhood). Results Prevalence of any condition in hospital records was 7.5% by early childhood, and 10.7% by middle childhood. Relative to peers without these presentations, small increases in risk of overall problems, and selected emotional, behavioral, and social problems, were apparent for children with any condition, and asthma specifically, in early and middle childhood. Large and pervasive effects were apparent for epilepsy, limited small effects in middle childhood only for allergies and anaphylaxis, and no increases in risk associated with type 1 diabetes examined in middle childhood. No condition was associated with increased risk of lacking supports. Conclusions Children with hospital records of chronic conditions, particularly epilepsy and asthma, might benefit from school-based care plans that integrate their physical and mental health support needs.

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Although parental criminal offending is a recognized risk factor for conduct problems among offspring, its impact on the continuity and discontinuity of children’s behavioural and emotional difficulties during the early development is less well known. We used data from a large, population-based record-linkage project to examine the relationship between parental offending and the continuity and discontinuity of children’s conduct, attentional, and emotional difficulties from early to middle childhood while also considering the role of timing of the parental offending exposure. Method: Data for 19,208 children and their parents were drawn from the New South Wales Child Development Study. Multinomial regression analyses tested associations between mother’s and father’s history and timing of any and violent offending, and patterns of continuity or discontinuity in offspring emotional, conduct, and attentional difficulties between ages 5 and 11 years. Results: Maternal and paternal offending each conferred a significantly increased risk of all the patterns of developmental difficulties, including those limited to age 5 only (remitting problems), to age 11 only (incident problems), and to difficulties present at both ages 5 and 11 years (persisting problems). Greatest odds were observed for persisting conduct problems. Paternal offending that continued through early and middle childhood had the greatest association with child difficulties, while the timing of maternal offending had a less prominent effect on child developmental difficulties. Conclusion: Parental offending is a strong risk factor for early and pervasive behavioural and emotional problems in offspring, and may be a key indicator of high risk for later antisocial behaviour.

The intergenerational transmission of criminality is well established. However, few intergenerational studies in Australia have examined the link between parents’ offending and their children’s behaviour. Even fewer have used large enough samples to examine serious maternal offending. This study uses a sample of over 21,000 Australian children and their parents to determine the prevalence and co-occurrence of offending among mothers and fathers, and the relationship between parental offending and children’s conduct problems at age 11. The study found that parental offending increases a child’s likelihood of conduct problems, and the offending most strongly associated with child conduct problems is maternal violent offending. It also found that the intergenerational transmission of antisocial behaviour begins early, highlighting the importance of intervention for at-risk children and programs targeted at mothers as well as fathers.

Background: Childhood maltreatment is associated with early childhood developmental vulnerabilities. However, the extent to which higher levels of child protection responses confer benefit to developmental competencies, and the impact of earlier timing of first reports in relation to early childhood vulnerability remains unclear. Objective: We examined associations between early developmental vulnerabilities and (1) the highest level of child protection response (where OOHC was deemed the highest response among other types of reports/responses), and (2) the developmental timing of the first child protection report. Participants and Setting: Participants included 67,027 children from the New South Wales Child Development Study, of whom 10,944 were reported to child protection services up to age 5 years. Methods: A series of Multinomial Logistic Regressions were conducted to examine focal associations. Results: Children with substantiated maltreatment reports showed the strongest odds of vulnerability on three or more developmental domains (adjusted OR = 4.90; 95% CI = 4.13–5.80); children placed in OOHC showed slightly better physical, cognitive and communication competencies (adjusted ORs from 1.83 to 2.65) than those with substantiated reports that did not result in OOHC placements (adjusted OR from 2.77 to 3.67), when each group was compared to children with no child protection reports. Children with first maltreatment reports occurring in the first 18 months of life showed the strongest likelihood of developmental vulnerabilities on three or more developmental domains (adjusted OR = 3.56; 95% CI = 3.15–4.01) relative to children with no child protection reports. Conclusion: Earlier reports of maltreatment may signal the need for targeted remediation of early developmental competencies to mitigate early developmental difficulties.

Background: Cross-agency administrative data can improve cost-effective triage systems for child protection and other human service delivery. Objective: To determine the minimum set of cross-agency indicators that could accurately classify placement in out-of-home-care (OOHC)before age 13–14 years. Participants and setting: Participants were 72,079 Australian children (mean age = 13.16 years; SD = 0.37; 51.4% male)and their parents, for whom linked administrative records spanning the years 1994–2016 were available for analysis within the ‘New South Wales Child Development Study’. Methods: First, a series of logistic regression analyses were conducted to examine associations between cross-agency (health, justice, education)risk indicators and membership of the sub-cohort of 1239 children who had an OOHC placement prior to age 13–14 years, relative to (1)the sub-cohort of 55,473 children who had no previous contact with child protection services, and (2)the sub-cohort of 15,367 children who had been reported to child protection services but had no record of OOHC placement. We then explored the classification characteristics associated with a smaller combination of risk factors, and the utility of specific familial risk factors, for classifying membership of the OOHC subgroup. Results: A combination of six risk indicators evident before OOHC placement can classify children placed in OOHC with approximately 95% accuracy, and the presence of at least four of these risk indicators provides excellent specificity (99.6%). Conclusions: A combination of risk factors observable in administrative datasets held by multiple government agencies may be used to target support services to prevent entry into OOHC for children from vulnerable families.

Objective: We examined associations between developmental vulnerability profiles determined at the age of 5 years and subsequent childhood mental illness between ages 6 and 13 years in an Australian population cohort. Methods: Intergenerational records from New South Wales (NSW) Government Departments of Health and Child Protection spanning pre-birth to 13 years of age were linked with the 2009 Australian Early Development Census records for 86,668 children. Mental illness indices for children were extracted from health records between 2009 and 2016 (child’s age of 6–13 years). Associations between mental disorder diagnoses and membership of early childhood risk groups, including those with established ‘special needs’ (3777, 4.3%) at school entry, or putative risk classes delineated via latent class analysis of Australian Early Development Census subdomains – referred to as ‘pervasive risk’ (N = 3479; 4.0%), ‘misconduct risk’ (N = 5773; 6.7%) or ‘mild generalised risk’ (N = 9542; 11%) – were estimated using multinomial logistic regression, relative to children showing ‘no risk’ (N = 64,097; 74%). Poisson regression models estimated the relative risk of a greater number of days recorded with mental health service contacts among children in each Australian Early Development Census risk group. Adjusted models included child’s sex, socioeconomic disadvantage, child protection contacts and parental mental illness as covariates. Results: The crude odds of any mental disorder among children aged 6–13 years was increased approximately threefold in children showing pervasive risk or misconduct risk profiles at the age of 5 years, and approximately sevenfold in children with special needs, relative to children showing no risk; patterns of association largely remained after adjusting for covariates. Children with special needs and the misconduct risk class used mental health services over a greater number of days than the no risk class. Conclusion: Patterns of early childhood

Background Elevated levels of pro-inflammatory cytokines are consistently reported in schizophrenia (SZ) and bipolar-I disorder (BD), as well as among individuals who have been exposed to childhood trauma. However, higher levels of inflammatory markers in these disorders are yet to be investigated with respect to levels of exposure to different types of childhood trauma.Methods Participants were 68 cases with a diagnosis of schizophrenia/schizoaffective disorder (SZ), 69 cases with a diagnosis of psychotic BD and 72 healthy controls (HC). Serum levels of interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified, and childhood trauma exposure was assessed with the Childhood Trauma Questionnaire.Results The SZ group had significantly higher levels of IL-6, TNF-α and CRP when compared with the HC group (all p < 0.05, d = 0.41-0.63), as well as higher levels of TNF-α when compared with the BD group (p = 0.014, d = 0.50); there were no differences between the BD and HC groups for any markers. Exposure to sexual abuse was positively associated (standardised β = 0.326, t = 2.459, p = 0.018) with levels of CRP in the SZ group, but there were no significant associations between any form of trauma exposure and cytokine levels in the HC or BD groups.Conclusions These results contribute to the evidence for a chronic state of inflammation in SZ but not BD cases. Differential associations between trauma exposure and levels of pro-inflammatory cytokines across the diagnostic categories suggest that trauma may impact biological (stress and immune) systems differently in these patient groups.

This paper describes the development of a brief school-based instrument designed for use in research and in educational practice. The Survey of School Promotion of Emotional and Social Health differentiates states of high, moderate, and low implementation of whole-school policies and practices that promote the emotional and social health of students. The instrument measures the extent to which a school has implemented policies and practices in four health-promoting domains: (a) creating a positive school community, (b) teaching social and emotional skills, (c) engaging the parent community, and (d) supporting students experiencing mental health difficulties. Responses were gathered via an online survey of Principals in almost 600 Australian primary schools in New South Wales. Preliminary psychometric properties of the instrument, and the development of an implementation index using latent class analysis, are described. The final 13-item version of the survey has broad applicability for use by researchers and evaluators for comparative and multivariate analyses. School leadership may find it useful as a brief tool to guide the identification of target areas for whole-school improvement across the four important health-promoting domains.

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Background: Fetal exposure to infectious and noninfectious diseases may influence early childhood developmental functioning, on the path to later mental illness. Here, we investigated the effects of in utero exposure to maternal infection and noninfectious diseases during pregnancy on offspring developmental vulnerabilities at age 5 years, in the context of estimated effects for early childhood exposures to infectious and noninfectious diseases and maternal mental illness. Methods: We used population data for 66,045 children from an intergenerational record linkage study (the New South Wales Child Development Study), for whom a cross-sectional assessment of five developmental competencies (physical, social, emotional, cognitive, and communication) was obtained at school entry, using the Australian Early Development Census (AEDC). Child and maternal exposures to infectious or noninfectious diseases were determined from the NSW Ministry of Health Admitted Patients Data Collection (APDC) and maternal mental illness exposure was derived from both APDC and Mental Health Ambulatory Data collections. Multinomial logistic regression analyses were used to examine unadjusted and adjusted associations between these physical and mental health exposures and child developmental vulnerabilities at age 5 years. Results: Among the physical disease exposures, maternal infectious diseases during pregnancy and early childhood infection conferred the largest associations with developmental vulnerabilities at age 5 years; maternal noninfectious illness during pregnancy also retained small but significant associations with developmental vulnerabilities even when adjusted for other physical and mental illness exposures and covariates known to be associated with early childhood development (e.g., child's sex, socioeconomic disadvantage, young maternal age, prenatal smoking). Among all exposures examined, maternal mental illness first diagnosed prior to childbirth conferred the greatest odds

© Copyright 2018, Mary Ann Liebert, Inc. Though the positive association between a connection to the natural environment and well-being is well established, few studies have examined this association in children, and none have explored whether this relationship remains when accounting for other factors that affect well-being, such as social supports, attention, and empathic skills. The current study aims to address this gap. Data are drawn from the New South Wales Child Development Study (NSW-CDS) and comprise a representative sample of 26,848 children who completed a self-report survey of mental health and well-being when aged approximately 11 years. Multiple regression analysis indicated that, after adjusting for covariates (i.e., social supports, empathy, attention, socioeconomic status, and sex), connection to nature was positively, albeit weakly, associated with two indicators of well-being: self-satisfaction and prosocial behavior. Social supports had the strongest relationship with self-satisfaction, while empathy had the strongest relationship with prosocial behavior. Based on our findings, and that of previous research, we suggest that developing a connection to nature can slightly improve well-being and may complement or augment other well-being and education-based programs. Future research should examine whether the relationship between connection to nature and well-being is influenced by proximity to green spaces, experiences of nature, and age.

This study examined the structure of the Best Start Kindergarten Assessment (Best Start) of literacy and numeracy, with the aim of confirming a two-factor measure of attainment at school entry comparable in structure to standardised measures of literacy and numeracy administered in later school years. Administrative data from the 2009 Best Start were obtained from the New South Wales Department of Education for 37,734 children aged ∼5 years (i.e. as they entered their first year of compulsory schooling) as part of the New South Wales Child Development Study. Exploratory and confirmatory factor analyses were performed on the 11 Best Start scales using a split half methodology, with the findings supporting a two-factor solution underpinning literacy and numeracy attainment. The availability of this two-factor Best Start measure of literacy and numeracy at school entry, which precedes the repeated national assessments conducted later in the primary and high school years, facilitates research to examine pathways of academic performance over time.

Background The single nucleotide polymorphism (SNP) rs1344706 [A > C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. Methods Using both univariate (voxel-based morphometry, VBM; cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy individuals selected from the Australian Schizophrenia Research Bank. Results Neither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy individuals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri; (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis/precentral gyrus; and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. Conclusions Contrary to some – but not all – previous findings, this study of a large sample of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in sample sizes and ethnicities may account for discrepant findings between the present and previous studies.

Background Childhood trauma is a risk factor for psychosis. Deficits in response inhibition are common to psychosis and trauma-exposed populations, and associated brain functions may be affected by trauma exposure in psychotic disorders. We aimed to identify the influence of trauma-exposure on brain activation and functional connectivity during a response inhibition task. Methods We used functional magnetic resonance imaging to examine brain function within regions-of-interest [left and right inferior frontal gyrus (IFG), right dorsolateral prefrontal cortex, right supplementary motor area, right inferior parietal lobule and dorsal anterior cingulate cortex], during the performance of a Go/No-Go Flanker task, in 112 clinical cases with psychotic disorders and 53 healthy controls (HCs). Among the participants, 71 clinical cases and 21 HCs reported significant levels of childhood trauma exposure, while 41 clinical cases and 32 HCs did not. Results In the absence of effects on response inhibition performance, childhood trauma exposure was associated with increased activation in the left IFG, and increased connectivity between the left IFG seed region and the cerebellum and calcarine sulcus, in both cases and healthy individuals. There was no main effect of psychosis, and no trauma-by-psychosis interaction for any other region-of-interest. Within the clinical sample, the effects of trauma-exposure on the left IFG activation were mediated by symptom severity. Conclusions Trauma-related increases in activation of the left IFG were not associated with performance differences, or dependent on clinical diagnostic status; increased IFG functionality may represent a compensatory (overactivation) mechanism required to exert adequate inhibitory control of the motor response.

Background: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). Results: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. Conclusions: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.

Background: Maternal smoking during pregnancy and parental offending are both linked to adverse offspring outcomes. Few studies have examined how these exposures together influence diverse offspring outcomes in early childhood. Aims: To examine associations between quantity of prenatal maternal smoking and frequency of maternal offending and offspring behavioural and cognitive outcomes at age 5 years. Methods: Over 66,000 Australian children (mean age 5.6 years) were drawn from an intergenerational data linkage study. Unadjusted and adjusted logistic regressions were conducted for the two key exposures (maternal prenatal smoking and mother having at least two criminal convictions) and offspring behavioural and cognitive vulnerabilities. Population attributable fractions (PAFs) were also estimated for each outcome for the two exposures. Results: Prenatal smoking and maternal offending were, separately and together, associated with most of the developmental vulnerabilities examined, even after adjusting for other familial and prenatal risk factors. PAFs for prenatal smoking ranged from 5.3% to 15.8%, and PAFs for maternal offending ranged from 3.4% to 11.8% across the offspring outcomes. Conclusions: Maternal smoking during pregnancy and maternal offending were uniquely associated with a range of offspring vulnerabilities, but mothers who smoked during pregnancy tended to experience multiple problems that should also be considered as indicators of child vulnerabilities. While early behavioural difficulties were evident in these children, it was striking that they were also likely to have cognitive vulnerabilities. Early intervention to support cognitive development in these children may minimise their risk of academic underachievement, long-term disadvantage, and even offending.