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.

Our preliminary findings indicate an involvement of inflammatory processes in the pathophysiology of psychosis and cognitive deficits in 22q11.2DS and are in line with the accumulating evidence for the role of neuroinflammation in nonsyndromic schizophrenia.

About one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia. Notably, a full-blown psychotic disorder is usually preceded by subthreshold symptoms. Therefore, it is important to identify early signs of psychosis in this population, a task that is complicated by the intellectual disabilities typically seen in 22q11.2DS. We aimed to identify subthreshold psychotic symptoms that distinguish 22q11.2DS from other neurodevelopmental disorders. The study included two independent cohorts from Tel Aviv and Philadelphia. 22q11.2DS (N=171) and typically developing (TD; N=832) individuals were enrolled at both sites and further compared to two groups with intellectual disabilities: Williams syndrome (WS; N=21) in the Tel Aviv cohort and idiopathic developmental disabilities (IDD; N=129) in the Philadelphia cohort. Participants and their primary caregivers were interviewed with the Structured Interview for Prodromal Symptoms (SIPS) and psychopathologies were assessed using standardized tools; general cognitive abilities were assessed with the Computerized Neurocognitive Battery. Negative/disorganized subthreshold syndrome was significantly more common in the 22q11.2DS group than in the WS (OR=3.90, 95% CI=1.34–11.34) or IDD (OR=5.05, 95% CI=3.01–10.08) groups. The 22q11.2DS group had higher scores than the two intellectual disabilities groups on several SIPS negative items, including avolition and decreased expression of emotion. Overall, there were few significant correlations between level of cognitive deficits and severity of negative symptoms in 22q11.2DS and only in the Tel Aviv cohort. Our findings suggest that 22q11.2DS individuals at the age of risk for developing psychosis should be closely monitored for negative symptoms.