| Schizophrenia is a serious mental disorder characterized by the abnormal mental functions and disturbed behaviors, which characteristically appears as a series of clinical features, such as positive and negative symptoms, and disturbances in basic cognitive functions. It belongs to complex diseases and its cause remains unknown. It is quite imperative to establish a procedure of treating and preventing schizophrenia, since the illness causes heavy economical and social burdens to families and societies.The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway. The present study attempted to investigate the gene coding for the ACSL gene family, which is an important enzyme for the synthesis of membrane phospholipids.We recruited 233 Chinese parent-offspring trios of Han descent and detected 7 SNPs at the ACSL loci. The family trios consist of healthy fathers, healthy mothers and affected offspring with schizophrenia.SNPs were genotyped using PCR-based RFLP analysis. The haplotype-based haplotype relative risk (HHRR) test and the transmission disequilibrium test (TDT) were applied to detect allelic association between SNPs and schizophrenia.In addition, combined effects of paired SNPs were tested by the UNPHASED program . The patients were divided into two groups according to the clinical psychotic symptoms. We analyzed psychotic symptoms versus allelic and genotypic frequency for each SNP.The details of methodology and major results obtained in this study is as follows:1 Association between SNPs and schizophrenia1.1 The TDT analysis :The TDT analysis showed that rs2102862 and rs6717500 were associated with schizophrenia (P<0.05). The rs2102862(C) present in the ACSL2 locus was a C to T base change and heterozygous parents have excessively transmitted allele C to their affected offspring, suggesting that the haplotype containing rs2102862(C)allele may carry disease-causing variant for schizophrenia. The rs6717500(A) present in the ACSL3 locus was a A to G base change and heterozygous parents have excessively transmitted allele A to their affected offspring, suggesting that the haplotype containing rs6717500(A)may carry disease-causing variant for schizophrenia.1.2 The HHRR analysis:The HHRR analysis revealed an allelic association between the two SNPs , rs2102862 and rs6717500, and schizophrenia. This finding was consistent with TDT result.1.3 Analysis for clinical subgroups:The patients were classified according to features that they have or have not a certain positive symptom and the extent of a certain negative symptom. The results showed that rs2102862, rs3749232, rs6717500, rs2419621and rs10885346 were associated with schizophrenia. Since the time at which SNPs occurred differs, each SNP may have its own genetic heritage with a different haplotype and non-random association. They may affect each other in allele frequency distribution, so as to reduce the power to detect their association with the illness. The advantage of clinical subgroup analysis is to limit the interference from different LD signals to reduce the false negative results and validate the hypothesis of genetic heterogeneity.1.4 Analysis for haplotype transmission The analysis for multi-SNP hapoltype transmission is essential to discover a specific haplotype or chromosome possibly carrying a gene for schizophrenia.The globalχ2 test of the two-SNP haplotype systems showed that the rs2102862 -rs3749232 haplotype system was associated with schizophrenia.The 1-df test for individual haplotypes also showed that the rs2102862 (T)-rs3749232 (G) haplotype was excessively non-transmitted (P < 0.05), suggesting that it may contain the disease-resistant allele. The rs2102862 (C)-rs3749232 (G) haplotype was excessively transmitted and this haplotype may contain a susceptible allele for schizophrenia.1.5 The conditional testThe results of conditional test show that the combination of rs2102862 and rs6717500 could enhance susceptibility to illness.2 The association between SNPs and psychotic symptoms of schizophreniaTo investigate the association between SNPs and positive and negative symptoms of schizophrenia, the SPSS program was applied for the statistical analysis. The results were shown as follows:2.1 The association between rs2102862 and psychotic symptoms of schizophrenia The distribution of allele and genotype frequencies was significantly different between the patients with delusion of jealousy and those without the symptom (P=0.004; P=0.001 respectively). It suggested that the 2102862 was associated with delusion of jealousy,one of positive symptoms of schizophrenia.2.2 The association between rs3749232 and psychotic symptoms of schizophreniaThe distribution of allele frequencies was significantly different between the patients with delusion of being revealed and those without the symptom (P = 0.034). It suggested that the rs3749232 was associated with the delusion of being revealed, one of positive symptoms of schizophrenia.2.3 The association between rs6717500 and psychotic symptoms of schizophreniaThe distribution of allele frequencies was significantly different between the patients with delusion of sin and those without the symptom (P = 0.009) . It suggested that rs6717500 was associated with delusion of sin , the positive symptoms of schizophrenia. The distribution of genotype frequencies was significantly different between the patients with genuine auditory hallucination, delusion of sin, delusion of negation and delusion of love and those without the symptom (P = 0.044, P = 0.003, P = 0.034 and P = 0.019). It suggested that rs6717500 was associated with genuine auditory hallucination, delusion of sin, delusion of negation and delusion of love, the positive symptoms of schizophrenia.2.4 The association between rs10885346 and psychotic symptoms of schizophreniaThe distribution of allele frequencies and genotype frequencies was significantly different between the patients with delusion of influence and those without the symptoms (P = 0.002 and P = 0.010). It suggested that rs10885346 was associated with delusion of influence.2.5 The association between rs615305 and psychotic symptoms of schizophreniaThe distribution of genotype frequencies was significantly different between the patients with delusion of jealousy and those without the symptom (P = 0.037). It suggested that rs615305 was associated with the delusion of jealousy.2.6 The association between rs2419621 and psychotic symptoms of schizophreniaThe quantitative trait analysis showed that rs2419621 was associated with poverty of thought (P = 0.031).3 The association between SNPs and schizophrenia in genderThe HHRR analysis showed that the parents have excessively transmitted rs2102862 allele C to their female affected offspring (P = 0.025).The result suggested that rs2102862 was associated with schizophrenia in females. The parents have excessively transmitted rs6717500 allele A to their male affected offspring (P = 0.0004).The result suggested that rs6717500 was associated with male schizophrenia.The parents have excessively transmitted rs2419621 allele T to their male affected offspring (P = 0.024).The result suggested that rs2419621 was associated with schizophrenia in males.Taken together, the present results suggest that the ACSL gene family may contribute to the etiology of schizophrenia, but the other genes of small effect can't be ruled out. Five SNPs, including rs2102862,rs6717500,rs3749232,rs10885346 and rs615305, were associated with some positive symptoms of schizophrenia. The rs2419621 was found to be associated with poverty of thought that were classified as one of three negative symptoms. These findings are very important for elucidating the genetic mechanisms of schizophrenia at a molecular level, and also for the development of genetic diagnosis, new drugs for the treatment of the illness and prediction of schizophrenia risk. |
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