Association Between The Histone Deacetylases Gene Family Gene Polymorphisms And Schizophrenia

Schizophrenia is a serious mental disease, which occurs in young adulthood. Itseriously threatens human being’s mental and physical health and brings heavyeconomic burden to the society and families. The prevalence of schizophrenia incrowd is about1%, and until now the etiology and pathogenesis of schizophrenia arenot clear. The research of family, twin, and foster sub-study showed that geneticfactors played an important role in the pathogenesis of schizophrenia, with theheritability of60%to80%. Schizophrenia not only does not match the traditionalMendelian inheritance, but also it is not a single-gene genetic disease. It may becaused by the co-function of the multi-gene or minor genes together, and to someextent, it maybe influenced by environmental factors which played a role in theprogress of the disease occurring. Based on candidate gene strategy, histonedeacetylases (HDACs) family genes which played a very important role in epigeneticmechanism were selected to explore the associations between HDACs polymorphismsand schizophrenia by family trios. The results of our study would be useful to showmechanism of molecular genetics of schizophrenia.PurposeThe purpose of our study is to explore the associations between HDACs familygenes polymorphisms and schizophrenia by the methods of the advancedbioinformatics, molecular biology and biostatistics. We aim to reveal the possiblemolecular genetics mechanism of the susceptibility genes of schizophrenia.MethodA total of208family trios consisting of fathers, mothers and affected offspring withschizophrenia were recruited as subject. There were125males and83females inpatients. Bioinformatics methods was used to select10tag HDACs SNPs, including4SNPs on HDAC2(rs10499080, rs6568819, rs2499618and rs13204445),2SNPs onHDAC3(rs11741808and rs2530223) and4SNPs on HDAC8(rs12690254,rs3012655, rs497551and rs544484). Sequenom Mass Array mass spectrometry array was performed to detect the individual genotype and allele. The chi-square (χ2)goodness-of-fit test was used to analyze the Hardy-Weinberg equilibrium (HWE) forgenotypic distribution. Allelic association for a single tag SNP was analyzed byfamily-based association tests, including the haplotype-based haplotype relative risk(HHRR) test and the transmission disequilibrium test (TDT). UNPHASED analysisplatform was used to test the balance level between the two sites and haplotype. Thechi-square test was used to test the associations between the10tag SNPs on theHDACs family genes and clinical symptoms and clinical subgroups of theschizophrenia. The PGMDR software was used to test the gene-gene interactions ofthe HDACs gene with schizophrenia.Result(1) Hardy-Weinberg equilibrium testSix tag SNPs on the HDAC2and HDAC3were selected. Except for thers10499080on HDAC2, the genotype frequencies of the other five tag SNPs were allin Hardy-Weinberg equilibrium (P>0.05). Because HDAC8was located on Xchromosome, the genotype frequencies of four tag SNPs on it were not inHardy-Weinberg equilibrium (P <0.05).(2) HHRR analysisThe results of the HHRR analysis showed that the frequent distributions of nine tagSNPs allele gene on HDACs between the patient group and their parents group werenot statistically different (all P>0.05), which revealed that there were no associationsbetween these nine tag SNPs on HDACs and schizophrenia. Among female patients,the frequent distribution of rs3012655on HDAC8was significantly different(P=0.039) between case group and control group.(3) TDT analysisThe results of TDT analysis showed that the probabilities of two different alleleswhich transmitted from heterozygotic parents to affected offsprings did not biasedfrom50%(P>0.05). It revealed that there was no association between HDACs geneand schizophrenia. We also found that two different alleles of rs11741808on HDAC3transmitted from heterozygotic parents to affected offsprings biased from50%infemale patients (P=0.038).(4) Multi-point combination analysisThe frequent distributions of three types of haplotype of the three tag HDAC2 SNPs, one haplotype of HDAC3, and six types of haplotype of thefour tag HDAC8SNPs were not significantly associated with schizophrenia (P>0.05).(5) Correlation analysis of clinical symptoms and schizophreniaIn total sample, locus of rs13204445on HDAC2, loci of rs11741808and rs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms of schizophrenia. Locus ofrs2530223on HDAC3was significantly correlated with negative symptom ofschizophrenia.Among male patients, loci of rs6568819and rs13204445on HDAC2, loci ofrs11741808and rs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms ofschizophrenia. Loci of rs2530223on HDAC3and rs3012655on HDAC8weresignificantly correlated with negative symptom of schizophrenia.Among female patients, loci of rs6568819and rs2499618on HDAC2, locus ofrs2530223on HDAC3, and loci of rs12690254, rs3012655, rs497551and rs544484on HDAC8were significantly correlated with positive symptoms of schizophrenia.Loci of rs2499618on HDAC2and rs3012655on HDAC8were significantlycorrelated with negative symptom of schizophrenia.(6) Correlation analysis of clinical subtypes and schizophrenia.In total sample, all the loci of HDAC2and HDAC3were not significantlyassociated with paranoid schizophrenia and unclassified schizophrenia. Loci ofrs11741808and rs2530223on HDAC3were significantly correlated with paranoidschizophrenia.(7) Interactions between genesPGMDR software was performed to analyze interactions between nine tag SNPs onHDAC2, HDAC3and HDAC8, respectively. The results showed that five-stagemultiple gene interaction model of rs2530223-rs6568819-rs12690254-rs497551-rs544484was the optimal model (P<0.05) to show associations between genes andschizophrenia.ConclusionAbove all, five pointed were concluded:(1) locus of rs3012655on HDAC3wereassociated with schizophrenia among females;(2) HDAC2, HDAC3and HDAC8might associated with some positive symptoms and negative symptoms of schizophrenia;(3) some loci on HDAC2, HDAC3and HDAC8might associated withparanoid schizophrenia and unclassified schizophrenia;(4) interactions betweenrs2530223-rs6568819-rs12690254-rs497551-rs544484might associated withschizophrenia;(5) there were genetically heterogeneous and clinical heterogeneity inschizophrenia.