Transmission analysis of presynaptic and neurodevelopmental candidate gene variants in schizophrenia and bipolar affective disorder

Schizophrenia and bipolar affective disorder are common psychiatric illnesses that exhibit strong heritability, yet are complicated by a polygenic mode of transmission with evidence of significant genetic heterogeneity. Despite decades of research, little replicated evidence has accumulated to suggest direct, causative mutations or pathways predisposing to illness. Abnormal neurodevelopment is implicated in these disorders through studies showing morphometric changes in various brain regions in affected individuals, together with alterations of cell density, alignment, and connectivity.;Many post-mortem and expression microarray-based investigations have identified misexpression of central presynaptic molecules in both schizophrenia and bipolar disorder in the absence of associated degenerative processes or abnormal cell density/morphology. Three critical presynaptic molecules controlling neurotransmitter release are SNAP-25, synaptobrevin/VAMP, and syntaxin1a, forming a complex whose assembly (regulated through numerous accessory proteins) allows fusion of the synaptic vesicle with the plasma membrane, and subsequent release of neurotransmitter into the synaptic cleft.;This investigation tested the hypothesis that sequence variation at presynaptic and further candidate loci would demonstrate linkage disequilibrium with schizophrenia or bipolar disorder based upon misexpression, functional studies, genetic linkage/association, and involvement in neurotransmission, as specific for each analysis. Alleles and haplotypes were evaluated within 10 genes in schizophrenia, and 4 in bipolar disorder, including: SNAP25, STX1A , VAMP1, SYN2, SYN3, NSF, SNAP29, COMT, NOTCH4 , and GSCL, with analyses based on sex, suicidality, symptom onset, medication response, and epistasis (gene-gene interaction) considered vital for examination of putative contributions to the psychiatric phenotype. Among the findings of this research, significant association was detected between SNAP25 alleles, haplotypes, and suicide attempts with bipolar disorder, SNAP29 and GSCL (in Portuguese) alleles with schizophrenia, NOTCH4 alleles and haplotypes in African-Americans with schizophrenia, genotypes of SYN3 and STX1A with schizophrenia symptom onset, and SNAP25 genotypes with antipsychotic drug response.;Further research on SNAP25 in depressive disorders and neuroleptic response is warranted, together with examination of STX1A and other presynaptic molecules as phenotypic modifiers. These findings can be applied to risk evaluation and treatment decisions, as well as constitute a framework for the study of other biological systems and complex neuropsychiatric disorders.