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Warnica W.,Clinical Genetics Research Program | Merico D.,Applied Genomics | Costain G.,Clinical Genetics Research Program | Alfred S.E.,Clinical Genetics Research Program | And 6 more authors.
Biological Psychiatry | Year: 2015

Background MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs.Methods Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11.2 CNVs. We also performed a gene-set enrichment analysis of the predicted miRNA target genes.Results The schizophrenia group was enriched for the proportion of individuals with a rare CNV overlapping a miRNA (3.29-fold increase over comparison subjects, p <.0001). The presence of a rare CNV overlapping a miRNA remained a significant predictor of schizophrenia case status (p =.0072) in a multivariate logistic regression model correcting for total CNV size. In contrast, comparable analyses correcting for CNV size showed no enrichment of rare CNVs overlapping protein-coding genes. A gene-set enrichment analysis indicated that predicted target genes of recurrent CNV-overlapped miRNAs in schizophrenia may be functionally enriched for neurodevelopmental processes, including axonogenesis and neuron projection development. Predicted gene targets driving these results included CAPRIN1, NEDD4, NTRK2, PAK2, RHOA, and SYNGAP1.Conclusions These data are the first to demonstrate a genome-wide role for CNVs overlapping miRNAs in the genetic risk for schizophrenia. The results provide support for an expanded multihit model of causation, with potential implications for miRNA-based therapeutics.

Brzustowicz L.M.,Rutgers University | Bassett A.S.,Clinical Genetics Research Program | Bassett A.S.,University of Toronto | Bassett A.S.,A+ Network
Frontiers in Genetics | Year: 2012

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. © 2012 Brzustowicz and Bassett.

Philip N.,Multidisciplinary Center for Prenatal Diagnosis | Bassett A.,Clinical Genetics Research Program | Bassett A.,University of Toronto | Bassett A.,A+ Network
Behavior Genetics | Year: 2011

22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions, particularly schizophrenia which develops in about 20-25% of individuals with a chromosome 22q11.2 microdeletion. From the initial discovery of the syndrome, associated developmental delays made it clear that changes in brain development were a key part of the expression. Once patients were followed through childhood into adult years, further neurobehavioural phenotypes became apparent, including a changing cognitive profile, anxiety disorders and seizure diathesis. The variability of expression is as wide as for the myriad physical features associated with the syndrome, with the addition of evolving phenotype over the developmental trajectory. Notably, variability appears unrelated to length of the associated deletion. Several mouse models of the deletion have been engineered and are beginning to reveal potential molecular mechanisms for the cognitive and behavioural phenotypes observable in animals. Both animal and human studies hold great promise for further discoveries relevant to neurodevelopment and associated cognitive, behavioural and psychiatric disorders. © 2011 Springer Science+Business Media, LLC.

Husted J.A.,University of Waterloo | Ahmed R.,University of Waterloo | Chow E.W.C.,Clinical Genetics Research Program | Chow E.W.C.,University of Toronto | And 3 more authors.
Schizophrenia Research | Year: 2010

There is some evidence that childhood adversity may be associated with the expression of schizophrenia but whether genetic risk affects this finding is unknown. We investigated the history of early trauma in 194 subjects from 24 multiply affected families where schizophrenia was previously shown to be associated with a functional allele in the NOS1AP gene. In subjects with schizophrenia (n=79), only events prior to the onset of psychosis were considered. Generalized estimating equation models that adjusted for familial clustering were used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Subjects with narrowly defined schizophrenia were more likely than their unaffected family members to have a history of early trauma (adjusted OR=4.17, 95% CI=1.52, 11.44). The results were similar after adjusting for the NOS1AP risk genotype (adjusted OR=3.57, 95% CI=1.32, 9.65) and for maternal or paternal history of schizophrenia (adjusted ORs=3.27, 95% CI=1.45, 7.38; 4.38, 95% CI=1.61, 11.91, respectively). The results suggest that childhood trauma is associated with expression of schizophrenia independent of measured genetic susceptibility and may be a candidate for gene-environment research using genetic variants. © 2010 Elsevier B.V.

Vorstman J.A.S.,University Utrecht | Breetvelt E.J.,University Utrecht | Thode K.I.,Malcolm Grow Medical Center | Chow E.W.C.,Clinical Genetics Research Program | And 3 more authors.
Schizophrenia Research | Year: 2013

Background: Copy number variants (CNVs) associated with neuropsychiatric disorders are increasingly being identified. While the initial reports were relatively specific, i.e. implicating vulnerability for a particular neuropsychiatric disorder, subsequent studies suggested that most of these CNVs can increase the risk for more than one neuropsychiatric disorder. Possibly, the different neuropsychiatric phenotypes associated with a single genetic variant are really distinct phenomena, indicating pleiotropy. Alternatively, seemingly different disorders could represent the same phenotype observed at different developmental stages or the same underlying pathogenesis with different phenotypic expressions. Aims: To examine the relation between autism and schizophrenia in patients sharing the same CNV. Method: We interviewed parents of 78 adult patients with the 22q11.2 deletion (22q11.2DS) to examine if autistic symptoms during childhood were associated with psychosis in adulthood. We used Chi-square, T-tests and logistic regression while entering cognitive level, gender and age as covariates. Results: The subgroup of 22q11.2DS patients with probable ASD during childhood did not show an increased risk for psychosis in adulthood. The average SRS scores were highly similar between those with and those without schizophrenia. Conclusions: ASD and schizophrenia associated with 22q11.2DS should be regarded as two unrelated, distinct phenotypic manifestations, consistent with true neuropsychiatric pleiotropy. 22q11.2DS can serve as a model to examine the mechanisms associated with neuropsychiatric pleiotropy associated with other CNVs. © 2012 Elsevier B.V.

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