Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n=35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p adj =6.73x10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.
Prodromal positive psychotic symptoms and anxiety are two strong risk factors for schizophrenia in 22q11.2 deletion syndrome (22q11DS). The analysis of large-scale brain network dynamics during rest is promising to investigate aberrant brain function and identify potentially more reliable biomarkers. We retrieved and examined dynamics of large-scale functional brain networks using innovation-driven co-activation
Low hippocampal volume is a consistent finding in schizophrenia and across the psychosis spectrum. However, there is a lack of studies investigating longitudinal hippocampal development and its relationship with psychotic symptoms. The 22q11.2 deletion syndrome (22q11DS) has proven to be a remarkable model for the prospective study of individuals at high risk of schizophrenia to unravel the pathophysiological processes predating the onset of psychosis. Repeated cerebral MRIs were acquired from 140 patients with 22q11DS (53 experiencing moderate-to-severe psychotic symptoms) and 135 healthy controls aged from 6 to 35 years and with up to 5 time points per participant. Hippocampal subfield analysis was conducted using FreeSurfer-v.6 and FIRST-FSL. Then, whole hippocampal and subfield volumes were compared across the groups. Relative to controls, patients with 22q11DS showed a remarkably lower volume of all subfields except for CA2/3. No divergent trajectories in hippocampal development were found. When comparing patients with 22q11DS exhibiting psychotic symptoms to those without psychosis, we detected a volume decrease during late adolescence, starting in CA1 and spreading to other subfields. Our findings suggested that hippocampal volume is consistently smaller in patients with 22q11DS. Moreover, we have demonstrated that patients with 22q11DS and psychotic symptoms undergo a further decrease in volume during adolescence, a vulnerable period for the emergence of psychosis. Interestingly, CA2/3, despite being affected in patients with psychotic symptoms, was the only area not reduced in patients with 22q11DS relative to controls, thus suggesting that its atrophy exclusively correlates with the presence of positive psychotic symptoms. 25 32 hippocampal volume has been found in patients across the 33 psychosis spectrum [3, 10, 11], comprising first-episode 34 psychosis patients (FEP) [12, 13] and subjects at high/ 35 ultrahigh (UHR) risk for psychosis [14, 15]. However, a 36 meta-analysis has recently shown that there was no evi-37 dence for a significant reduction in the whole hippocampal Q3 38 volume in patients at clinical high risk for psychosis [16], 39 suggesting that only subtler changes might be detectable 40 early in disease progression. Indeed, a dose-response rela-41 tionship depending on the stage of the disease has been 42 found in individuals at UHR for psychosis [10].
Converging evidence suggests that psychosis emerges from the complex interaction of genetic and environmental factors. Stressful life events (SLEs) play a prominent role in combination with coping strategies and with a dysfunctional hypothalamus-pituitary-adrenal axis (HPAA). It has been proposed that the framework of schizotypy might help disentangle the interaction between genetic and environmental factors in the pathogenesis of psychosis. Similarly, 22q11.2 deletion syndrome (22q11DS) is considered as a genetic model of psychosis vulnerability. However, SLE and coping strategies remain largely unexplored in 22q11DS. Moreover, the HPAA has not been systematically investigated in this population. Here, we explored the correlation between SLE, emotional coping strategies, schizotypal personality traits, subthreshold psychotic symptoms in a sample of 43 healthy controls (HCs) compared with 59 individuals with 22q11DS. In the latter, we also explored the correlation with pituitary volume as estimated from structural magnetic resonance imaging. We found that SLE and negative coping strategies were correlated with schizotypal personality traits in both HCs and 22q11DS, and with psychotic symptoms in the 22q11DS group only, whereas reduced pituitary volume correlated with general psychopathology. Moreover, dysfunctional coping mediated the effect of SLE on schizotypal personality traits and psychotic symptoms in 22q11DS. Our findings recapitulate evidence in nonsyndromic patients and confirm the central role of stress and coping in the pathogenesis of psychosis. More broadly, they highlight the importance of environmental factors in the pathway to psychosis in 22q11DS, suggesting a strong rationale for the implementation of stress and particularly coping-oriented interventions in this population.
Autism spectrum disorders (ASD) and non-affective psychoses such as schizophrenia are commonly acknowledged as discrete entities. Previous research has revealed evidence of high comorbidity between these conditions, but their differential diagnosis proves difficult in routine clinical practice due to the similarities between core symptoms of each disorder. The prevalence of comorbid non-affective psychoses in individuals with ASD is uncertain, with studies reporting rates ranging from 0% to 61.5%. We therefore performed a systematic review and pooled analysis of the available studies reporting the prevalence of non-affective psychosis in ASD. Fourteen studies, including a total of 1708 participants, were included, with a weighted pooled prevalence assessed at 9.5% (95% CI 2.6 to 16.0). In view of significant heterogeneity amongst the studies, subgroup analyses were conducted. We observed higher prevalence of non-affective psychoses among ASD inpatients versus outpatients, when operationalised criteria were used, and in studies with smaller sample sizes, whereas the figures were comparable between children and adults with ASD. Our results suggest that future studies involving larger samples should implement both operationalized criteria and specific scales for the assessment of psychotic symptoms in individuals with ASD. A deeper understanding of both differential and comorbid features of ASD and non-affective psychosis will be required for the development of optimized clinical management protocols.
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