Microarray Analysis Of Altered Gene Expression And The Study Of Genetic Susceptibility To Tumor Suppressor APC, TXNIP In Schizophrenia

Objective The study was to detect gene expression profiles of leucocytes in schizophrenia using high throughput microarray analysis, in order to screen out susceptibility genes of schizophrenia.Methods Leukocytes in peripheral blood of six schizophrenic patients and six normal controls were collected and total RNA was abstracted. The cDNA probes of patients and normal control were prepared by labeling cell RNA with Cy5 and Cy3 with reverse transcription respectively. The microarrays with 8464 genes were hybridized against the cDNA probe mixture, and the fluorescent signals were scanned. Results Thirteen genes were down regulated in all schizophrenia patients when the ratio of Cy5/Cy3 signal was more than 2.0 or less than 0.5; and 31 genes expression altered when more than 1.5 or less than 0.7. Out of the 31 genes, 29 genes showed decreased expression and 2 genes elevated expression in schizophrenics. All altered genes were expressed in brain and 8 of them were expressed in prefrontal lobe S-11 of schizophrenics. 11 out of all changed genes were located at susceptibility locus of schizophrenia and other 3 changed genes were located at susceptibilitity locus of bipolar disorder. Two tumor suppressor genes APC and TXNIP, which were located at schizophrenia susceptibility locus 5q21-22 and 1 q21 -22 respectively, were changed in leukocytes of all schizophrenic patients.Conclusions The results provided preliminary evidence that some genes involved in neuronal development, apoptosis, myelination formation , neurotransmission, tumor suppression and immune function may have different expressions in schizophrenia from normal people.Objective The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia.Methods We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 recurrent patients taking antipsychotic medication, 29 first-episode drug-naive patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). We also investigate the relationship between expression levels of APC and clinical traits according to PANSS scores. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT), haplotype-based haplotype relative risk ( HHRR) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC.Results APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC expression levels in both positive symptoms group and compound symptoms group were significantly higher than healthy control group (P=0.014, pP=0.002). There was no significant difference between negative symptoms group and healthy control group however.TDT showed that the three SNPs (rs2229992, rs42427, rs465899) were significantly associated with schizophrenia [TDT: A2=4.23 (PO.05), 4.15 ( PO.05 ), and 8.49 (PO.01) respectively; HHRR: ^ = 5.54 (PO.05) , 4.40 (PO.05) , and 9.79(PO.01), respectively]. We found a significant association between the APChaplotypes from rs2229992-rs42427-rs465899 and schizophrenia (GlobalX2 = 44.376, df=7, P<0.00\, Three (T-G-T, C-A-T, C-A-C) of them were significantly associated with schizophrenia. One of them is C-A-T, which has a frequency of 57% and has the strongest association with schizophrenia(X2= 15.04, i><0.00 1).Conclusions These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia.Objective To confirm the findings of microarray analysis, and investigate the effect of antipsychotic medication on TXNIP gene expression level, we here identified thioredoxin-interacting protein gene (TXNIP), a tumor metastasis suppressor gene, as a risk factor for schizophrenia.Methods We measured expression levels of TXNIP in the leukocytes from 30 recurrentrecurrent patients taking antipsychotic medication, 30 first-episode drug-naive patients, and 30 healthy controls using absolute TaqMan real-time quantitative polymerase chain reaction (PCR). The expression quantitation of TXNIP of unknown samples was measured by standard curve. Further, for assessment of the relationship between TXNIP expression level and clinical traits, we divided subgroups from first-episode drug-naive group and recurrent patients taking antipsychotic medication group respectively according to PANSS scores, dose of antipsychotics and family history.Results (1) The average TXNIP expression level in leukocytes of all schizophrenics group was significantly lower than that of healthy control group by 30.2 % (P=0.032 ). That of the recurrent taking antipsychotic group was also lower than that of healthy control group by 94.0% (P^O.000) , while that of the first-episode drug-naive group was higher than that of healthy control group (by 33.6%, P=0.009) and recurrent group (P=0.000) ; (2) There were no significant differences on TXNIP expression levels among positve ^ negative and compound symptom subgroups in both first-episode drug-naive patients and recurrent group taking antipsychotic medication. (3) There were no significant differences on TXNIP gene expression levels between mild and severe symptoms subgroups. (4) There were no correlation between TXNIP gene expression level and positve > negative and total scores of PANSS. (5) In recurrent group, TXNIP expression level in patients with family history group was significant lower than that of without family history group (iJ=0.006) . (6) Pearson correlate analysis showed that there was no significant correlation between TXNIP...