Genetics in Schizophrenia and Bipolar Disorder

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A genetic variant associated with multiple psychiatric disorders drives changes in a brain network that may increase an individual’s risk of developing bipolar disorder and schizophrenia. Genetic analysis and neuroimaging in samples of adults with schizophrenia, early-onset bipolar disorder and healthy controls — in addition to postmortem analysis of brain tissue from schizophrenia patients — to demonstrate that a variant of a gene involved in neurotransmission is associated with both disorders.
They found that this genetic variation changes the expression of the SNAP25 protein in the brain, which may impact information processing between brain regions involved in regulating emotions. Consistent with this idea, the variant was associated with larger amygdala volume and altered prefrontal-limbic connectivity.



Abstract
A multi-level functional study of a SNAP25 at-risk variant for bipolar disorder and schizophrenia
The synaptosomal associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected controls, we showed that the SNAP25b:SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multi-level functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early onset bipolar disorder and schizophrenia.
SIGNIFICANCE STATEMENT
Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open avenue in the development of personalized treatments. Recent studies have cumulated evidence that the SNARE complex and more specifically the SNAP25 protein may be involved in psychiatric disorders. Here, our multi-level functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically-driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder, and confirm the shared genetic vulnerability between these two disorders.

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