Bertolin, Cinzia (2008) Caratterizzazione genetico-molecolare di un campione di soggetti affetti da disturbi dello spettro schizofrenico/bipolare provenienti da Chioggia. [Tesi di dottorato]
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In order to identify susceptibility loci for schizophrenia (SZ) and bipolar disorder (BPD), we collected clinical informations and biological sample of patients affected by SZ, BPD and schizoaffective disorder (SA), in collaboration with Mental Health Centre of Chioggia.
Recent findings, emerging from genetic studies, support the evidence that these diseases share a number of susceptibility genes. Accordig to this theory, we carried out genetic and molecular analysis to better undestand schizophrenia and its associated disorders in their genetic context.
By performing these analysis we were able to:
1) Collect clinical and anagraphical informations about the 40 pedigrees with high loading for schizophrenia and bipolar disorder. For each family, pedigree structure was traced back to tree generations using both church registers and demographical records. Additionally, we genotyped microsatellite markers on chromosome Y to evaluate the possibility of common male ancestor.
2) Assess the weight of genetic component and the mode of inheritance of SZ/BPD, in the pedigrees. We performed a complex segregation analysis (in collaboration with Prof. Scapoli); the results suggest that a main additive gene, plus a residual polygenic component is the best fitting hereditary model for the collected sample (Scapoli et al., 2006).
3) Find susceptibility loci with a genome wide search (GWS) in 16 multigenerational pedigrees with a high loading of the diseases (57 subjects). We genotyped 489 microsatellite markers (465 in the first scan and 24 in the fine-mapping analysis) and we calculated, using a multipoint approach, LOD score parametric and non parametric (NPL). The higher LOD score was obtained on chromosome 15q26, with a peak on marker D15S1014 (NPL=3.05), that reaches the statistical criteria for suggestive linkage (genomic P value of 0.07).
In this region (15q26) mapped the gene ST8SIA2. Recently, two SNPs located in the promoter of the gene were reported in association with schizophrenia in a Japanese and Chinese sample. In order to test the frequencies of these polimorfisms, we performed a preliminary analysis in a sample of 156 Italian subjects: 56 patients and 100 healthy subjects (50 from Chioggia and 50 from other Italian regions). The SNPs analyzed resulted to be rare or not polymorphic at all, both in Chioggia and in the general Italian population, so they are unlikely to be directly involved in schizophrenia in our population.
In order to test the possibility that some families share minor susceptibility loci not identified in the previous analysis, we evaluated linkage data for each single family separately. We found that 2 of the 16 pedigrees showed high LOD score values in 3q24-27 and 18q23, therefore in these regions a further investigations, increasing the marker density and analysing the haplotypes, were carried out. In this way, we were able to reveal on chromosome 3q24-27 a putative common haplotype shared between a subset of families. With a similar approach on chromosome 18q23 we were not able to identify a good segregation shared among other pedigrees.
4) Evaluate a possible involvement of mitochondrial polymorphisms in the pathogenesis of psychiatric disease. We characterized the mt haplogroups (Hg) and haplotypes (HVI region) of 86 index cases; the distribution of the Hg were similar to those reported for a large sample of the general Italian population so we were not able to find any significant differecies in the distribution of the haplogrups. Interestingly, we identified 12 lineages that seem to be shared between different families. These data suggest that:
- families that share the same mtDNA could have a same maternal ancestor;
- the shared mitochondria could carry a particular set of polymorphisms that influence the genetic predisposition to SZ and BPD.
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