Genetic Variations of PIP4K2A Confer Vulnerability to Poor Antipsychotic Response in Severely Ill Schizophrenia Patients

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.

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness

“…Patients with CGI-Improvement score (CGI-I) 2 or decrease of two points from baseline score were grouped as complete responders (CR) and patients with CGI-I ! 3 or more were grouped as incomplete responders (IR) [Gupta et al, 2009;Gupta et al, 2012;Gupta et al, 2013;Kaur et al, 2014]. Overall,193 (45.63%) …”

“…We further explored gene-gene interactions between 48 polymorphisms in the genes (GRM3, SLC1A1, SLC1A2, SLC1A3, and SLC1A4) investigated in the present study and 53 genetic variants of previously published genes (BDNF, SLC6A3, RGS4, PIP4K2A, and PI4KA) (Kaur et al, 2014). Multifactor dimensionality reduction (MDR v. 2.0) method was applied to assess the possible epistatic interaction among these SNPs [Moore et al, 2006].…”

“…The investigation of genetic interactions may be essential in understanding the genetic architecture of complex schizophrenia disorder and differential therapeutic outcome. Thus, we further examined the statistical epistasis between SNPs of glutamatergic pathway genes and other signaling molecules (BDNF, RGS4, PI4KA, PIP4K2A, and SLC6A3) that have been previously genotyped in same population [Kaur et al, 2014].…”

Shared and distinct alterations of white matter tracts in remitted and nonremitted patients with schizophrenia

“…To date, treatment effectiveness in different patients remains unclear (Lieberman et al, ). Different treatment outcomes may be attributed to the genetic and molecular heterogeneity of patients (Kaur et al, ; Mirnics, Middleton, Marquez, Lewis, & Levitt, ), which may have signatures in the brain structures and functions (Egan et al, ). Therefore, a brain correlate that is characteristic of the treatment outcomes is desirable to avoid unnecessary treatment of nonremission, to ensure an adequate trial for patients who are likely to benefit from taking antipsychotics, and to improve the long‐term treatment outcomes (Correll, Malhotra, Kaushik, McMeniman, & Kane, ).…”

BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis

“…Included studies were published between 2003 and 2015 and sample sizes ranged from 50 to 591 antipsychotic - treated patients. Clinical response to antipsychotic drugs was assessed by the Brief Psychiatric Rating Scale (BPRS) [, , 20,34–36], the Positive and Negative Syndrome Scale (PANNS) [22,26,27], the Clinical Global Impression Scale (CGI) [25] and the Global Assessment Scale (GAS) [21]. The average percentage of MINORS score was 47% (range 38–56%, Table 1), indicating that the overall methodological quality was moderate.…”