Methylome-wide and meQTL analysis helps to distinguish treatment response from non-response and pathogenesis markers in schizophrenia.

Schizophrenia is a complex condition with entwined genetic and epigenetic risk factors, posing a challenge to disentangle the intermixed pathological and therapeutic epigenetic signatures. To resolve this, we performed 850K methylome-wide and 700K genome-wide studies on the same set of schizophrenia patients by stratifying them into responders, non-responders, and drug-naïve patients. The key genes that signified the response were followed up using real-time gene expression studies to understand the effect of antipsychotics at the gene transcription level. The study primarily implicates hypermethylation in therapeutic response and hypomethylation in the drug-non-responsive state. Several differentially methylated sites and regions colocalized with the schizophrenia genome-wide association study (GWAS) risk genes and variants, supporting the convoluted gene-environment association. Gene ontology and protein-protein interaction (PPI) network analyses revealed distinct patterns that differentiated the treatment response from drug resistance. The study highlights the strong involvement of several processes related to nervous system development, cell adhesion, and signaling in the antipsychotic response. The ability of antipsychotic medications to alter the pathology by modulating gene expression or methylation patterns is evident from the general increase in the gene expression of response markers and histone modifiers and the decrease in class II human leukocyte antigen (HLA) genes following treatment with varying concentrations of medications like clozapine, olanzapine, risperidone, and haloperidol. The study indicates a directional overlap of methylation markers between pathogenesis and therapeutic response, thereby suggesting a careful distinction of methylation markers of pathogenesis from treatment response. In addition, there is a need to understand the trade-off between genetic and epigenetic observations. It is suggested that methylomic changes brought about by drugs need careful evaluation for their positive effects on pathogenesis, course of disease progression, symptom severity, side effects, and refractoriness.

Contribution from MHC-Mediated Risk in Schizophrenia Can Reflect a More Ethnic-Specific Genetic and Comorbid Background.

The immune system seems to play a significant role in the development of schizophrenia. This becomes more evident with the emerging role of MHC complex and cytokines in schizophrenia. In the recent past, several GWAS have implied that the 6p21 region was associated with schizophrenia. However, the majority of these studies were performed in European populations. Considering tremendous variations in this region and the probability of South Indian populations being quite different from the European gene-pool from an immunogenetic point, the present study was initiated to screen SNPs in the 2.28 MB region, spanning the extended MHC locus, in 492 cases and controls from a South Indian population. We found a very strong association of rs3815087 with schizophrenia at both allelic and genotypic levels with a 7.3-fold increased risk in the recessive model. Interestingly, the association of none of the earlier reported GWAS hits, such as rs3130375, rs3131296, rs9272219, or rs3130297 were found to be replicable in our study population. rs3815087 lies in the 5'UTR region of the psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene, which further suggests that inflammatory processes might be an important common pathogenic pathway leading to both schizophrenia and psoriasis. The study hints at ethnic specific gene-environment interaction in determining the critical threshold for disease initiation and progression.

DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia.

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.

Association of dopamine receptor polymorphisms with schizophrenia and antipsychotic response in a South Indian population.

BACKGROUND: Alterations in the dopamine transmission and receptor density are hypothesized in the pathophysiology of schizophrenia but ethnic disparities are reported to exist in disease association and therapeutic response to psychotropic medication. Antipsychotics have higher binding affinity to D2 subtype of dopamine receptor. DRD2 Cys311, TaqIB1 and TaqIA1 variants are considered to have either reduced affinity for dopamine and hypo-dopaminergic activity. METHODS: We examined the role of Taq1B, Taq1D, S311C, H313H and Taq1A polymorphisms of DRD2 gene in schizophrenia and antipsychotic treatment response in 213 patients and 196 controls from a homogenous South Indian population. A more detailed genotype phenotype association analysis was carried out to understand the disease in terms of its socio-cultural factors. RESULTS: H313HTT genotype was found to be associated with schizophrenia (P = 0.004) while TaqIB1B1 genotype was significantly associated with higher psychopathology score. When treatment response was considered H313HCC, TaqIA2A2 and Taq1D1D1 had higher mean improvement scores. TaqID1D1 and H313HTT genotype were found to be significantly higher in responders than in nonresponder group. Distinct shift in the LD patterns of responder and non-responder group was observed. Certain symptoms were characteristic of our patient population. Following medication the scores and presentation of these symptoms tend to vary in the responder and non-responder groups. CONCLUSION: Based on genotype phenotype correlations it can be suggested that certain polymorphisms can be defined for their critical functions in disease and their role in treatment response in South Indian population. The present study suggests that in addition to ethnic bias, socio-cultural factors should also be considered while evaluating genotype phenotype correlations, in association and treatment response to complex disorders like schizophrenia.