Abstract
DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P = .004, allele P = 0.022) and rs2228611 (genotype P = 0.004, allele P = 0.022) were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P = 0.023) and allele (P = 0.0063) increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P = 0.027, allele P = 0.033) was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P = 0.009). DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026) confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia.
Highlights
Schizophrenia is one of the most debilitating mental disorders affecting 1% of the world population
Observations from association analyses of SNPs in DNMT1, DNMT3A, DNMT3B, and DNMT3L indicated that DNMT1 rs2114724 and rs2228611 were strongly associated with schizophrenia at allelic and genotypic level (Table 3, Table S1)
In the present study we report that the polymorphisms in the DNMT1, rs2114724 and rs2228611 are significantly associated with schizophrenia in Malayalam speaking south Indian population
Summary
Schizophrenia is one of the most debilitating mental disorders affecting 1% of the world population. The disorder has a well established heritability, while studies done in identifying the genetic susceptibility factors were invariantly inconsistent. Genome wide association studies and Linkage analyses have tried to identify susceptibility loci but, no common genetic variant confers in itself more than twice the risk in susceptibility for schizophrenia in general population [1]. Recent advances in the field of epigenetics have increased understanding of this interaction by identifying molecular mechanisms that mediate environmental influences on gene expression and activity. Epigenetic mis regulations in response to a variety of environmental factors have been suggested as a mechanism to explain the increasing risk of schizophrenia in adulthood [11]. Epigenetic mechanisms represent a form of cellular memory that contributes to either short- or longterm changes in neuronal function in response to a variety of behavioral experiences, environmental factors, and pharmacological stimuli [12]
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