Association of the PIK4CA Schizophrenia-Susceptibility Gene in Adults With the 22q11.2 Deletion Syndrome

Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 04/2009; 150B(3):430-3. DOI: 10.1002/ajmg.b.30827
Source: PubMed


The 22q11.2 deletion syndrome (22q11DS) is associated with an increased prevalence (20-30%) of schizophrenia. Therefore, it is likely that one or more genes within the 22q11.2 region are causally related to schizophrenia. Recently, a significant association with schizophrenia in the general population was reported for three SNPs in phosphatidyl-inositol-4-kinase-catalytic-alpha (PIK4CA), a gene located in the 22q11.2 region. In the current study, we tested the hypothesis that the same PIK4CA risk-alleles would be associated with schizophrenia in individuals with 22q11DS. Our analysis of the PIK4CA genotypes in a sample of 79 adults with typical 22q11.2 deletions, comparing those with schizophrenia to those without, revealed a significant association. Our findings represent an independent replication of the previously reported PIK4CA association with schizophrenia in the general population. Second, the results of this study indicate that variation at PIK4CA may be a relevant factor influencing the risk of schizophrenia in individuals with 22q11DS.

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Available from: Jacob A S Vorstman, Dec 27, 2014
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    • "There is also some evidence that polymorphisms in the PIK4CA gene which encodes for PI4KIIIα may be associated with genetic predisposition to schizophrenia [155] and psychiatric disorders associated with chromosome 22q.11 [156,157], although this may be confined to particular, restricted populations [158]. "
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    • "Since the "classical" candidate genes are not deleted in this person other candidate genes residing in the nested distal region may be responsible for the physical features and neuropsychiatric manifestations. For example, of the candidate genes that have been shown to be involved in cardiac malformations (HIRA, UFD1L, TBX1 and CRKL) [35-39]CRKL is one that is located in the distal deletion region and has been found to affect cardiac neural crest derivatives in mice [36]. Its loss may be the causative event for the CHD in this case. "
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    ABSTRACT: The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted. Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms. Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.
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    • "A variant in PIK4CA has been associated with risk of developing schizophrenia in individuals with 22q11.2DS, but alone is not sufficient to explain the variable penetrance of schizophrenia in these individuals (Vorstman et al., 2009). Sequencing studies of the deletion region will also help clarify this possibility. "
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    ABSTRACT: In humans, the most common genomic disorder is a hemizygous deletion of a 1.5-3 Mb region of chromosome 22q11.2. The resultant 22q11.2 deletion syndrome (22q11.2DS) can affect multiple organ systems, and most notably includes cardiac, craniofacial, and neurodevelopmental defects. Individuals with 22q11.2DS have a 20-25-fold risk of developing schizophrenia compared to individuals from the general population, making 22q11.2DS the strongest known molecular genetic risk factor for schizophrenia. Although the deleted region includes DGCR8, a gene coding for a miRNA processing protein, the exact mechanism by which this deletion increases risk is unknown. Importantly, several lines of evidence suggest that miRNAs may modulate risk for schizophrenia in other, non-22q11.2DS populations. Here we present a theory which mechanistically explains the link between 22q11.2DS, miRNAs, and schizophrenia risk. We outline the testable predictions generated by this theory and present preliminary data in support of our model. Further experimental validation of this model could provide important insights into the etiology of both 22q11.2DS and more common forms of schizophrenia.
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