Association Between DNA Methylation Quantitative Trait Loci And Schizophrenia With Famine In Early Life

Schizophrenia is a common type of mental illness and one of the most serious and complex neuropsychiatric disorders.Schizophrenia ranks first in mental illness,and the lifetime prevalence in the population is 1%.Schizophrenia is highly disabling and difficult to completely control the symptoms,which brings a heavy burden on individuals,families,and society.The first onset of it usually happens at adolescents.The pathogenesis of schizophrenia is complicated and has not yet been fully elucidated.Most studies think that schizophrenia is caused by the additive effect of multiple minor genes combined with environmental factors,in which genetic factors play a leading role.Although GWAS has achieved some success in the study of schizophrenia,the reproducibility of different studies is poor due to the large number of SNPs and the existence of heterogeneity.A number of studies have demonstrated that prenatal exposure to famine increases the risk of schizophrenia in adult children.Changes in DNA methylation are widely reported being involved in the development of the disease,and most studies agree that low levels of DNA hypomethylation are widespread in schizophrenic patients.In epigenetic studies of schizophrenia,DNA methylation may be an intermediate factor in mediating exposure to environmental risk factors and the development of neuropsychiatric disorders during maternal and childbirth,which leads to an increased risk of schizophrenia.Analyses of DNA methylation quantitative trait loci reveal that multiple SNP loci may be the key sites for controlling DNA methylation in schizophrenia patients,but there is no adequate validation in different population samples.ObjectivesIn this study,we investigated the relationship between DNA methylation quantitative trait loci?meQTL SNPs?mutations and the risk of schizophrenia based on people exposed to famine in early life.At the same time,a case-only study was conducted to explore the interaction between meQTL SNPs polymorphisms and exposure to famine in early life and investigate whether the meQTL SNPs locus polymorphisms have potential targets for the onset of schizophrenia.MethodsThis study was conducted in schizophrenia patients who were exposed to famine in early life?1960-1962?in northern China and who didn't experience famine in early life?1963-1965?,as well as healthy controls.A total of 960 samples were collected.Among them,225 cases were schizophrenia patients exposed to famine in early life,248 cases were healthy controls exposed to famine,267 cases were healthy controls not exposed to famine and 220 cases were schizophrenia patients not exposed to famines.The polymorphisms of rs2300149,rs3758543,rs61955196,and rs871925 were detected using the improved multiplex ligation detection reaction?iMLDR?SNP typing technique.Logistic regression was used to examine the association of meQTL SNPs with schizophrenia and the interaction between famine exposure and schizophrenia.GMDR software was utilized to analyze the association between genes and schizophrenia.Results1.The distribution of gender,marital status,occupation,educational level,and birthplace were statistically different between schizophrenia group and healthy control group,P<0.05.2.There was no significant difference in the distribution of smoking,drinking during mother's pregnancy and types of childbirth between schizophrenia group and healthy control group,P>0.05.3.The family history of schizophrenia patients and clinical symptoms of schizophrenia didn't relate with famine exposure?P=0.506,P=0.701?.The relation between clinical type of schizophrenia and famine exposure was statistically significant?P=0.002?,and the most significant was observed in those with undifferentiated type.4.The distribution of rs2300149 alleles and genotypes in schizophrenia group and healthy control group was not statistically significant?P>0.05?.The optimal genetic model of rs2300149 was a codominant model with OR_CT/CC=0.88,95%CI=0.66-1.18,OR_TT/CC=0.83,95%CI=0.56-1.22.5.The distribution of rs3758543 alleles and genotypes in schizophrenia group and healthy control group were not statistically significant?P>0.05?.The optimal genetic model of rs3758543 was an overdominant model(P=0.219,OR_GC/CC+GG=0.96,95%CI=0.90-1.02;).6.The distributions of rs61955196 locus and its allele were statistically significant in schizophrenia group and healthy control group under a co-dominant genetic model?P=0.038,0.034?.ORG/C=1.05,95%CI=1.00-1.10 was observed in both allele distributions.In the codominant model,OR_GG/CC=1.11,95%CI=1.01-1.22;OR_GC/CC=1.04,95%CI=0.97-1.11 were observed.The optimal genetic model was an implicit model(P=0.066,OR_GG/CC+GG=1.09,95%CI=0.99-1.19).7.The distribution of rs871925 alleles and genotypes in schizophrenia group and healthy control group were not statistically significant?P>0.05?.The optimal genetic model was an implicit model(P=0.336,OR_AA/AG+GG=1.04,95%CI=0.96-1.13).8.The interaction between the best genetic models of me QTL SNPs,genotypes of which distributions are statistically significant in schizophrenia patients and famine exposure in early life was not statistically significant?P>0.05?.9.The constructed multifactorial interaction model was not found to be associated with the risk of schizophrenia?P>0.05?.Conclusion1.There is an association between the clinical type of schizophrenia and famine exposure in early life.2.The allele and the codominant genetic model of rs61955196 locus are related to schizophrenia.3.The alleles and genotype distributions of rs2300149,rs3758543 and rs871925 are not related to schizophrenia.4.The best genetic models of meQTL SNPs?rs2300149?rs3758543?rs871925and rs61955196?and genotypes of which distributions are significantly different in schizophrenia patients have no interactions with famine exposure in early life.5.MeQTL SNPs?rs2300149?rs3758543?rs871925and rs61955196?Gene-gene interactions have nothing to do with the onset of schizophrenia.