In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood-brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947-11,816 genes (false-discovery rate-adjusted p < 0.05), including many transcripts that cannot be predicted significantly by a transcriptome-imputation method such as PrediXcan. BrainGENIE recapitulated measured diagnosis-related gene-expression changes in the brain for autism, bipolar disorder, and schizophrenia better than direct correlations from blood and predictions from PrediXcan. We developed a convenient software toolset for deploying BrainGENIE, and provide recommendations for how best to implement models. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.
Abstract Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2×10 −6 ) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6×10 −6 ) and manic symptoms (BD, p=2×10 −5 ), 2) BD subphenotypes: psychotic features (SCZ p=1.2×10 −10 , BD p=5.3×10 −5 ) and age of onset (SCZ p=7.9×10 −4 ). Finally, we show that psychotic features in BD has significant SNP-heritability (h 2 snp =0.15, SE=0.06), and a significant genetic correlation with SCZ (r g =0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes ( DARS2 , ARFGEF2 , DCAKD and GATAD2A ) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.
Boys with Attention Deficit Hyperactivity Disorder (ADHD, N = 50), Specific Learning Disorder (LD, N = 45), combined Specific Learning Disorder and ADHD (LD/ADHD, N = 25), and controls (N = 51) completed effortful and automatic information processing tasks based on Treisman and Gelade's (1980) "information integration theory". ADHD and LD/ADHD subjects did not differ from controls at baseline or under feedback and reward conditions, suggesting that they were investing similar levels of mental effort in the tasks. The LD group had a superior performance in the effortful task and an inferior performance in the automatic task compared with the other groups at baseline. The data suggest a potential method of distinguishing primary LD from learning difficulties that occur secondary to ADHD.
Background : Latent liability for schizophrenia (schizotypy) is expressed in various combinations of cognitive, psychological, and behavioural characteristics evident in the general population. Historical models propose that distinct classes of individuals expressing different forms of schizotypy may represent manifestations of differential levels of genetic and environmental risk for schizophrenia (or related illness). However, there has been little investigation of developmental models of schizotypy in childhood. Here, we sought to delineate latent profiles of schizotypy among children aged 11–12 years, and to examine associations between emerging schizotypal profiles and parental history of mental illness (as a proxy for genetic risk), early life trauma, and childhood contact with health services for mental illness up to age 13 years. Methods : Latent profiles of schizotypy were distinguished among 22,137 children (mean age=11.9 years) for whom intergenerational records of health service contact for mental illness and child protection reports were linked to the Middle Childhood Survey (MCS) within the NSW Child Development Study.1 Selected MCS items were used to index schizotypy across six domains (Unusual Experiences, Cognitive Disorganisation, Impulsive Nonconformity, Introversion, Dysphoria and Self-Other disturbance). Using Latent Profile Analyses (LPA), four groups emerged according to patterns of expression across these domains; membership of three putative schizotypy groups were examined in relation to the likelihood of being exposed to childhood maltreatment and parental mental illness, and the child’s own mental illness up to age 13 years, relative to the no risk group. Results : Four classes emerged from the LPA: (1) ‘schizotypy’ (n=1323; 6%); (2) ‘dysphoric pseudo-schizotypy’ (n=4261, 19%); (3) ‘introverted pseudoschizotypy’ (n=4473; 20%) and; (4) ‘no psychopathology’ (no-risk, n=12,080; 55%). Children in the schizotypy group had the greatest odds of being the subject of a child protection report (OR=2.9, 95% CI 2.6–3.3) and in contact with health services for mental illness by age 13 years (OR=2.7, 95% CI 2.2–3.3), relative to the no-risk group. The odds of child protection reports and childhood mental disorders were smaller, yet significantly increased, among dysphoric pseudo-schizotypy (ORs=1.9 and 1.8, respectively) and introverted pseudo-schizotypy (ORs=1.7 and 1.4, respectively), relative to the no-risk group. Parental mental illness exposure was greatest among the schizotypy (OR=2.3, 95% CI 2.0–2.6) subgroup, and was also increased in dysphoric pseudo-schizotypy (OR=1.6, 95% CI 1.5–1.8) and introverted pseudo-schizotypy (OR=1.4, 95% CI 1.3–1.5), relative to the no-risk group. Discussion : We provide evidence for distinct subtypes of children expressing different forms of schizotypy among a large Australian sample from the general population. The subgroup of children labeled ‘schizotypy’ (6%) characterized by high levels of cognitive disorganisation, impulsive non-conformity, introversion, and self-other disturbance may be at highest risk for developing schizophrenia or other mental illness in adulthood, and had a greater likelihood of childhood maltreatment and parental mental illness history, than other ‘pseudo-schizotypy’ groups.
Abstract Stress debriefing has been used extensively following traumatic events; however, there is little evidence of its effectiveness. This paper reports the effects of stress debriefing on the rate of recovery of 195 helpers (e.g., emergency service personnel and disaster workers) following an earthquake in Newcastle, Australia (62 debriefed helpers and 133 who were not debriefed). Post‐trauma stress reactions (Impact of Event Scale) and general psychological morbidity (General Health Questionnaire: GHQ‐12) were assessed on four occasions over the first 2 years postearthquake. There was no evidence of an improved rate of recovery among those helpers who were debriefed, even when level of exposure and helping‐related stress were taken into account. More rigorous investigation of the effectiveness of stress debriefing and its role in posttrauma recovery is urgently required.
This paper begins with a brief review of recent literature about relationships between offending behaviour and mental illness, classifying studies by the settings within which they occurred. The establishment and role of a mental health court liaison (MHCL) service is then described, together with findings from a 3-year service audit, including an examination of relationships between clients' characteristics and offence profiles, and comparisons with regional offence data. During the audit period, 971 clients (767 males, 204 females) were referred to the service, comprising 1139 service episodes, 35.5% of which involved a comorbid substance use diagnosis. The pattern of offences for MHCL clients was reasonably similar to the regional offence data, except that among MHCL clients there were proportionately more offences against justice procedures (e.g., breaches of apprehended violence orders [AVOs]) and fewer driving offences and "other offences". Additionally, male MHCL clients had proportionately more malicious damage and robbery offences and lower rates of offensive behaviour and drug offences. A range of service and research issues is also discussed. Overall, the new service appears to have forged more effective links between the mental health and criminal justice systems.
Understanding of the neurophysiological basis of cognitive, behavioural and perceptual disturbances associated with long-term cannabis use has grown dramatically. Exogenous cannabinoids alter the normative functioning of the endogenous cannabinoid system. This system is an important regulator of neurotransmission. Recent research has demonstrated abnormalities of the cannabinoid system in schizophrenia. The purpose of the present paper was to selectively review the links between cannabis use and psychosis, drawing upon recent epidemiological, clinical, cognitive, brain imaging and neurobiological research. The aim is to assist clinicians to probe more deeply into the newly unfolding world of cannabinoid physiology and to critically evaluate the potential role of cannabis in the onset and persistence of cognitive impairments and psychosis in otherwise healthy users and in schizophrenia.
Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.
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.To examine associations between child protection involvement and 3rd- and 5th-grade reading and numeracy attainment, while controlling multiple other adversities.Participants were 56,860 Australian children and their parents from the New South Wales Child Development Study with linked multi-agency records.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).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.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).
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