A MULTI-LEVEL FUNCTIONAL STUDY OF A SNAP25 AT-RISK VARIANT FOR BIPOLAR DISORDER AND SCHIZOPHRENIA

Background The synaptosomal associated protein SNAP25 is crucial for synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions. We recently identified a promoter variant in SNAP25, rs6039769, associated with bipolar disorder and gene expression in prefrontal cortex. Methods Here, we performed a genetic association study using this variation on two independent cohorts of 288 and 173 subjects with schizophrenia and 315 unaffected control individuals. We replicated our results using data from the schizophrenia group of the Psychiatric Genomics Consortium (PGC). Functional consequences combined both in vitro and post-mortem gene expression analysis on 30 patients with schizophrenia and 33 unaffected controls. Structural and functional magnetic resonance imaging in regards to SNAP25 genotypes was performed on 71 subjects and replicated on 121 individuals. Results We showed that rs6039769 was associated with schizophrenia in the two cohorts of patients as well as in the Caucasian population of the PGC cohort and demonstrated in vitro this variant was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis, we showed that the SNAP25b:SNAP25a ratio was increased in patients carrying the at-risk allele. Imaging genetics studies revealed that risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala. Discussion This multi-level functional study brings strong evidence for the functional consequences of this SNAP25 variation on the prefrontal-limbic network and the increased risk of developing associated psychiatric disorders.