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A case-control association study between genetic polymorphisms in the fads gene cluster and schizophrenia/schizoaffective disorder

Schizophrenia is a severe mental illness, a consequence of disturbances in brain biochemistry with subsequent disorders of important mental functions and behaviour and distinct defects in social, family and work functioning. There is no unique or uniform description in definition of schizophrenia, because definite etiologic, pathoanatomic or pathophysiologic criteria have not been identified so far. It seems that biological factors create predisposition for schizophrenia, while psychosocial factors act as precipitating factors. All genetic studies demonstrate a strong genetic basis of schizophrenia, with an increased risk for schizophrenia in relatives of a schizophrenic patient. One recent theory of schizophrenia is the phospholipid membrane hypothesis, based on disorders of phospholipid metabolism in brain of patients with schizophrenia, with dysfunction of neuronal cell membrane during development. Polyunsaturated fatty acids (PUFAs) are important components of membrane cells and neurological tissue. PUFAs, especially n-6 arachidonic acid (AA) and n-3 docosahexaenoic acid (DHA) are particularly important for the central nervous system structure and function. In postmortem brain tissue of schizophrenic patients deficits of PUFAs - DHA and/or AA, were detected. PUFA deficits in schizophrenia could be explained by genetic factors, such as polymorphisms in PUFA biosynthetic genes – those of the FADS (Fatty Acid Desaturases) gene cluster. In our work we analyzed three Single Nucleotide Polymorphisms – SNPs within the FADS1 FADS2 gene cluster, located on the chromosome 11: rs174556C>T - SNP1 - located in the intron region of the gene FADS1 ; rs3834458T>del - SNP2- located in CpG island in between genes FADS1 and FADS2 ; rs968567G>m - SNP3 - located in CpG island in between genes FADS1 and FADS2. These three SNPs were genotyped in 209 patients – 185 diagnosed with schizophrenia and 24 with schizoaffective disorder - and 81 healthy control subjects. Patients were recruited from Department of Psychiatry, Clinical Hospital Center Rijeka, Croatia (N=118) and Psychiatric Hospital Rab, Croatia (N=91), between 2007 and 2010. The existance and severity of schizophrenia symptoms of the patients were evaluated by psychiatrists using PANSS (Positive And Negative Symptom Scale) score. Analysis of the SNPs involved a PCR amplification of the SNP-containing sequences, followed by a digestion with appropriate restriction enzymes. Finally, agarose gel electrophoresis was carried out in order to determine SNP's genotypes of PCR products incubated with specific restriction enzymes. In this case-control study we determined frequencies of genotypes, minor alleles and haplotypes of the three selected SNPs in schizophrenic patients and control subjects. We also wanted to examine the possible association between the selected SNPs of the FADS gene cluster and schizophrenia. Data was analyzed by Chi-square test, by calculating the odds ratio (OR), 95% confidence intervals and Spearman's correlation, using statistical software - Statistica for Windows, version 8 (StatSoft, Inc). No significant differences were observed between frequencies of genotypes or haplotypes of the three SNPs in schizophrenia patients and control subjects. However, there is a trend of a lower frequency of the all-major allele (MaA) haplotype in schizophrenia patients, when compared to controls (p=0.071). We found no association between SNPs genotypes, all-major (composed of the major allele at each of the 3 loci) and all-minor (composed of the minor allele at each of the 3 loci) haplotypes, and clinical variables of schizophrenia, such as age of the first hospitalization due to schizophrenia symptoms, and PANSS scores. One possible limitation of our study is a relatively small sample size ; therefore, some further studies should include a larger sample of schizophrenia patients. Besides, our sample was rather nonselective when considering different types of schizophrenia, and thus, classification of patients based on the type of schizophrenia, or other criteria such as endophenotype, is recommended for future association analysis. Future researches regarding FADS gene cluster and its polymorphisms could also include exploration of dietary habits of study participants, and many other factors, that can have an influence on desaturase enzymes activity. All the work presented in this thesis was carried out in the Molecular Genetics Laboratory (Department of Biology and Medical Genetics, School of Medicine, Rijeka, Croatia).

schizophrenia; schizoaffective disorder; fatty acid desaturases; single nucleotide polymorphisms; PANSS

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