Prioritizing genetic contributors to cortical alterations in 22q11.2 deletion syndrome using imaging transcriptomics

22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = −1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants

Polygenic risk of psychosis and ventral striatal activation during reward processing in healthy adolescents

Importance: Psychotic disorders are characterized by attenuated activity in the brain’s valuation system in key reward processing areas, such as the ventral striatum (VS), as measured with functional magnetic resonance imaging. Objective: To examine whether common risk variants for psychosis are associated with individual variation in the VS. Design, setting, and participants: A cross-sectional study of a large cohort of adolescents from the IMAGEN study (a European multicenter study of reinforcement sensitivity in adolescents) was performed from March 1, 2008, through December 31, 2011. Data analysis was conducted from October 1, 2015, to January 9, 2016. Polygenic risk profile scores (RPSs) for psychosis were generated for 1841 healthy adolescents. Sample size and characteristics varied across regression analyses, depending on mutual information available (N = 1524-1836). Main outcomes and measures: Reward-related brain function was assessed with blood oxygen level dependency (BOLD) in the VS using the monetary incentive delay (MID) task, distinguishing reward anticipation and receipt. Behavioral impulsivity, IQ, MID task performance, and VS BOLD were regressed against psychosis RPS at 4 progressive P thresholds (P < .01, P < .05, P < .10, and P < .50 for RPS models 1-4, respectively). Results: In a sample of 1841 healthy adolescents (mean age, 14.5 years; 906 boys and 935 girls), we replicated an association between increasing psychosis RPS and reduced IQ (matrix reasoning: corrected P = .003 for RPS model 2, 0.4%variance explained), supporting the validity of the psychosis RPS models. We also found a nominally significant association between increased psychosis RPS and reduced MID task performance (uncorrected P = .03 for RPS model 4, 0.2%variance explained). Our main finding was a positive association between psychosis RPS and VS BOLD during reward anticipation at all 4 psychosis RPS models and for 2 P thresholds for reward receipt (RPS models 1 and 3), correcting for the familywise error rate (0.8%-1.9%variance explained). Conclusions and relevance: These findings support an association between psychosis RPS and VS BOLD in adolescents. Genetic risk for psychosis may shape an individual’s response to rewarding stimuli

Genetic and clinical analyses of psychosis spectrum symptoms in a large multiethnic youth cohort reveal significant link with ADHD

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8–22 years, the Philadelphia Ne

Psychosis Risk and Development: What Do We Know From Population-Based Studies?

Recent years have seen an advent in population-based studies in children, adolescents, and adults that examine the prevalence, etiology, and developmental trajectories of diverse subclinical psychopathological symptoms that pose a risk for the later development of severe mental illnesses. It is increasingly recognized that most categorically defined psychiatric disorders occur on a spectrum or continuum, show high heterogeneity and symptom overlap, and share genetic and environmental risk factors. We discuss neurodevelopmental underpinnings of psychosis spectrum symptoms and review brain morphometric and functional alterations as well as genetic liability for psychosis in individuals experiencing psychotic symptoms (PSs) in the general population. With regard to brain structure and function, findings of qualitatively similar alterations in individuals experiencing subthreshold PSs and individuals with overt psychotic disorders support the notion of a psychosis continuum. However, genetic and epidemiological studies have emphasized the overlap of PSs and other psychiatric illnesses. In particular, PSs during adolescence appear to be a nonspecific precursor of different psychopathological outcomes. Given the evidence presented in this review, we argue that findings from population-based studies are appropriate to guide policy-making to further emphasize public health efforts. Broadly accessible mental health programs are promising to make a difference in the field of adolescent mental health. However, the specific efficacy of these programs warrants further study, and caution is advised to not overpathologize potentially transient occurrence of mental health problems

Reduced higher dimensional temporal dynamism in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common single gene disorder resulting in multi-organ involvement. In addition to physical manifestations such as characteristic pigmentary changes, nerve sheath tumors, and skeletal abnormalities, NF1 is also associated with increased rates of learning disabilities, attention deficit hyperactivity disorder, and autism spectrum disorder. While there are established NF1-related structural brain anomalies, including brain overgrowth and white matter disruptions, little is known regarding patterns of functional connectivity in NF1. Here, we sought to investigate functional network connectivity (FNC) in a well-characterized sample of NF1 participants (n = 30) vs. age- and sex-matched healthy controls (n = 30). We conducted a comprehensive investigation of both static as well as dynamic FNC and meta-state analysis, a novel approach to examine higher-dimensional temporal dynamism of whole-brain connectivity.We found that static FNC of the cognitive control domain is altered in NF1 participants. Specifically, connectivity between anterior cognitive control areas and the cerebellum is decreased, whereas connectivity within the cognitive control domain is increased in NF1 participants relative to healthy controls. These alterations are independent of IQ.Dynamic FNC analysis revealed that NF1 participants spent more time in a state characterized by whole-brain hypoconnectivity relative to healthy controls. However, connectivity strength of dynamic states did not differ between NF1 participants and healthy controls.NF1 participants exhibited also reduced higher-dimensional dynamism of whole-brain connectivity, suggesting that temporal fluctuations of FNC are reduced. Given that similar findings have been observed in individuals with schizophrenia, higher occurrence of hypoconnected dynamic states and reduced temporal dynamism may be more general indicators of global brain dysfunction and not specific to either disorder. Keywords: Neurofibromatosis type 1, Functional connectivity, Dynamic functional network connectivity, Meta-state analysis, Group independent component analysi

Disruptions in White Matter Maturation and Mediation of Cognitive Development in Youths on the Psychosis Spectrum

BackgroundPsychosis onset typically occurs in adolescence, and subclinical psychotic experiences peak in adolescence. Adolescence is also a time of critical neural and cognitive maturation. Using cross-sectional data from the Philadelphia Neurodevelopmental Cohort, we examined whether regional white matter (WM) development is disrupted in youths with psychosis spectrum (PS) features and whether WM maturation mediates the relationship between age and cognition in typically developing (TD) youths and youths with PS features.MethodsWe examined WM microstructure, as assessed via diffusion tensor imaging, in 670 individuals (age 10-22 years; 499 TD group, 171 PS group) by using tract-based spatial statistics. Multiple regressions were used to evaluate age&nbsp;× group interactions on regional WM indices. Mediation analyses were conducted on four cognitive domains-executive control, complex cognition, episodic memory, and social cognition-using a bootstrapping approach.ResultsThere were age&nbsp;× group interactions on fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) and retrolenticular internal capsule. Follow-up analyses revealed these effects were significant in both hemispheres. Bilateral SLF FA mediated the relationship between age and complex cognition in the TD group, but not the PS group. Regional FA did not mediate the age-associated increase in any of the other cognitive domains.ConclusionsOur results showed aberrant age-related effects in SLF and retrolenticular internal capsule FA in youths with PS features. SLF development supports emergence of specific higher-order cognitive functions in TD youths, but not in youths with PS features. Future mechanistic explanations for these relationships could facilitate development of earlier and refined targets for therapeutic interventions

State-Dependent Functional Dysconnectivity in Youth With Psychosis Spectrum Symptoms.

Psychosis spectrum disorders are conceptualized as neurodevelopmental disorders accompanied by disruption of large-scale functional brain networks. Dynamic functional dysconnectivity has been described in patients with schizophrenia and in help-seeking individuals at clinical high risk for psychosis. Less is known, about developmental aspects of dynamic functional network connectivity (dFNC) associated with psychotic symptoms (PS) in the general population. Here, we investigate resting state functional magnetic resonance imaging data using established dFNC methods in the Philadelphia Neurodevelopmental Cohort (ages 8-22 years), including 129 participants experiencing PS and 452 participants without PS (non-PS). Functional networks were identified using group spatial independent component analysis. A sliding window approach and k-means clustering were applied to covariance matrices of all functional networks to identify recurring whole-brain connectivity states. PS-associated dysconnectivity of default mode, salience, and executive networks occurred only in a few states, whereas dysconnectivity in the sensorimotor and visual systems in PS youth was more pervasive, observed across multiple states. This study provides new evidence that disruptions of dFNC are present even at the less severe end of the psychosis continuum in youth, complementing previous work on help-seeking and clinically diagnosed cohorts that represent the more severe end of this spectrum

Prioritizing Genetic Contributors to Cortical Alterations in 22q11.2 Deletion Syndrome Using Imaging Transcriptomics.

22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = -1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants

Genetic and clinical analyses of psychosis spectrum symptoms in a large multiethnic youth cohort reveal significant link with ADHD.

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10-7) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories