Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients.

Harpreet Kaur,Sanjeev Jain,Ruchi Baghel,Sandeep Grover,Ajay Jajodia,Meenal Gupta,Ritushree Kukreti,Noam Shomron

doi:10.1371/journal.pone.0102556

Abstract

Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n = 355) and risperidone (n = 260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396) of PIP4K2A gene in incomplete responders (corrected p-value = 0.001; adjusted-OR = 3.19, 95%-CI = 1.46–6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR = 7.91, 95%-CI = 4.08–15.36). While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in incomplete responders with low severity (OR = 4.09, 95%-CI = 2.09–8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of PIP4K2A gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway.

Highlights

Schizophrenia is a heterogeneous mental illness with varying degrees of positive, negative and cognitive symptoms governed by both genetic and environmental factors
In the present study, we investigated 53 polymorphisms from five genes (RGS4, SLC6A3, PIP4K2A, Brain-derived neurotrophic factor (BDNF) and PI4KA) in 423 south Indian schizophrenia cases segregated into low and high severity of illness to assess their influence on antipsychotic response
Single nucleotide variations are known to account for 90% of genetic variability, we examined their effect on antipsychotic response in schizophrenia patients with variable degree of severity

Summary

Introduction

Schizophrenia is a heterogeneous mental illness with varying degrees of positive, negative and cognitive symptoms governed by both genetic and environmental factors. Polygenic involvement of genetic factors in the schizophrenia pathophysiology hinders the identification and characterization of causal genes that could develop as therapeutic targets. It is important to investigate the influence of genetic variation and clinical factors on therapeutic outcome in differentially affected schizophrenia individuals according to the disease severity [3]. These facts prompted us to identify variants that may influence drug response by investigating critical signaling molecules known to express in different brain regions, implicated in schizophrenia and drug response. We prioritized Brain-derived neurotrophic factor (BDNF), Solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3), Regulator of G-protein signaling 4 (RGS4), Phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A) and Phosphatidylinositol 4-kinase, catalytic, alpha (PI4KA)

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