Polymorphism in SNAP29 gene promoter region associated with schizophrenia

Abstract

Linkage studies indicate that chromosome 22q contains a locus, or loci, for schizophrenia (SZ) and bipolar disorder (BPD). Furthermore, the congenital disorder velo cardio facial syndrome (VCFS), which is usually caused by a 22q11 microdeletion, is associated with an increased prevalence of psychiatric disease, including SZ and BPD. One plausible candidate gene that maps to 22q11, in a region deleted in the most common form of VCFS, is SNAP29, a member of the SNAP-25 family of SNARE proteins. To search for possible functional mutations in SNAP29 that could be analyzed as candidates for 22q11-linked psychiatric problems, exons, intron-exon junctions and the promoter region were screened. No coding variants were found, although a silent mutation at codon 6 and three single nucleotide polymorphisms (SNPs) were identified in the 5Ј untranslated and promoter regions. One SNP, an A→G transition 849 nucleotides upstream of the transcription start site, showed a moderately significant difference in the distribution of alleles and genotypes in patients with SZ compared with controls (allele frequency: 2 = 5.57, 1 df, P = 0.018; genotype: 2 = 9.49, 2 df, P = 0.009; odds ratio = 1.59, 95% Cl = 1.08-2.34). No significant difference was found in patients with BPD. Although the functional significance of this mutation is not known, the tetranucleotide core sequence of the ets and IK2 families of transcription factors is altered as a result of the SNP. These data suggest that a mutation in the SNAP29 gene promoter region, or a mutation in linkage disequilibrium with the promoter SNP, may be involved in the pathogenesis of chromosome 22-linked SZ. Molecular Psychiatry (2001) 6, 193-201.

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

“…A polymorphism in the SNAP29 promoter region was found to be associated with schizophrenia in two different studies. 37,38 Interestingly, this polymorphism is also located in the first intron of PIK4CA. It may well be that the actual signal observed in the previous studies is due to strong LD between SNAP29 and PIK4CA gene variants and that it represents the same susceptibility locus identified in this study.…”

The SNARE protein SNAP‐29 interacts with the GTPase Rab3A: Implications for membrane trafficking in myelinating glia

“…Although this has not been directly proved yet, the SNAP-29 gene can be considered a candidate gene for velocardiofacial syndrome (VCFS, or 22q11 syndrome) with CNS abnormalities such as a smaller corpus callosum and reduced gyrification (Gothelf et al, 2008;Shprintzen, 2008). Also, schizoaffective disorders have been associated with a susceptibility locus on chromosome 22q11.2 (Saito et al, 2001;Wonodi et al, 2005;Prasad et al, 2008).…”

Multicenter linkage study of schizophrenia loci on chromosome 22q

“…Evidence for linkage or association to schizophrenia on chromosome 22q has been previously observed in some ethnically diverse samples. 13,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][59][60][61][62] The most parsimonious explanations of these results would be either that there are no schizophrenia susceptibility loci on chromosome 22q or that their population-wide effects are sufficiently weak that they cannot be reliably detected by linkage methods with our sample size. We would tentatively favor the second hypothesis, for two reasons:…”

“…It is possible that one or more genes on 22q11 will be associated with an early-onset phenotype, given the higher 22q11 microdeletion rate in children with schizophrenia, and the multiple premorbid cognitive and social impairments and distinguishing MRI features of children with VCFS and schizophrenia. 31 Evidence for association with schizophrenia has recently been reported for several 22q loci as shown in 37 Two groups have reported evidence for association between a microsatellite marker in the VCFS deletion region, D22S944, and schizophrenia. 38,39 Analyses of small samples of parent-proband trios 40 or cases and controls 41 showed no linkage disequilibrium between D22S278 and schizophrenia after correction for multiple tests.…”