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Variants and expression changes in PPAR-encoding genes display no significant association with schizophrenia.

ABSTRACT: A few studies suggested the contribution of PPARs to the etiology of schizophrenia (SCZ). However, it is still not clear whether variants in PPAR-encoding genes have a direct association with SCZ. The potential linkage between SCZ and the variants within PPAR encoding genes (PPARA, PPARD, and PPARG) was tested in a large cohort genome-wide association study (GWAS). Then, a mega-analysis was conducted using 14 gene expression profiling experiments in various human brain regions. Finally, the expression levels of the three PPAR-encoding genes were quantified in early-onset SCZ patients. Only one PPARG polymorphisms, rs62242085, presented a minor frequency deviation in the SCZ cohort (P-value = 0.035). None of the PPAR-encoding genes presented significant expression change within the brain regions profiled in 14 datasets acquired from different populations (P-value > 0.14) or in the whole blood of early-onset overall SCZ patients (P-value > 0.22). However, compared with healthy female controls, female early-onset SCZ patients presented a moderate but significant decrease in the expression level of PPARD (LFC = -0.55; P-value = 0.02) and a strong, but non-significant decrease in expression of PPARG (LFC = -1.30; P-value = 0.13). Our results do not support a significant association between variants in PPAR-encoding genes and SCZ, but suggest a necessity to explore the role of PPARD and PPARG in early SCZ phenotypes, specifically in females.

SUBMITTER: Li X

PROVIDER: S-EPMC7374279 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Variants and expression changes in PPAR-encoding genes display no significant association with schizophrenia.

Li Xinrong X Zhu Yue Y Keaton Maria M Baranova Ancha A Liu Sha S Hu Xiaodong X Li Qi Q Cheng Long L Zhou Peng P Cao Hongbao H Xu Yong Y

Bioscience reports 20200701 7

A few studies suggested the contribution of PPARs to the etiology of schizophrenia (SCZ). However, it is still not clear whether variants in PPAR-encoding genes have a direct association with SCZ. The potential linkage between SCZ and the variants within PPAR encoding genes (PPARA, PPARD, and PPARG) was tested in a large cohort genome-wide association study (GWAS). Then, a mega-analysis was conducted using 14 gene expression profiling experiments in various human brain regions. Finally, the expr ...[more]

PMID: 32643760

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Project description:Abstract Background: Schizophrenia is a lifelong debilitating mental illness often characterized by hallucinations, delusions, and disorganized thought and behavior. Currently, antipsychotic medications serve as the best treatment option for schizophrenia, but clinical responses to antipsychotic medications are highly variable. Therefore, the demand for reliable biological predictors is high. A glutamate and N-methyl-d-asparate (NMDA) receptor hypofunction model based on pharmacologic and genetic studies have been suggested as an approach to study the pharmacogenetics of antipsychotic medications. Previous studies have shown clozapine (CLZ) displaces NMDAR antagonists and enhances NMDAR mediated neurotransmission. Previously, our group (Taylor et al, 2016) investigated 8 SNPs in the NMDAR subunit gene GRIN2B with response to CLZ and one marker (rs1072388) was nominally significant. Taylor et al (in press) more recently found the glycine transporter 1 gene (SLC6A9, rs16831558) exhibited an allele dose-dependent improvement in the positive symptoms of CC-homozygotes compared to T-allele carriers (Puncorrected = .008, Pcorrected = .08). In our current study, we examined the GRIN2A receptor gene that was genome-wide significant in the GWAS of schizophrenia by Ripke et al (2014). A SNP marker from GRIN2A (rs992266789) and one from the glutamate receptor ionotropic delta 2 (GRID2, rs1875705) were selected for our association study of CLZ treatment response. Methods: We investigated rs9922678 and rs1875705 in relation to CLZ treatment response in a prospective study consisting of 170 Caucasian patients treated with CLZ for 6 months. Treatment response was evaluated using the 18-item Brief Psychiatric Rating Scale (BPRS), using either responder vs nonresponder status or continuous change scores. Baseline score was included as a covariate. All statistical analyses were performed using IBM SPSS. Results: No significant association was observed for rs9922678 and rs1875705 with BPRS total score and responder vs nonresponder status under genotypic, allelic, and additive models. Conclusion: Although no significant results were obtained from our current study, there is still strong neurobiological evidence suggesting involvement of the glutamate system in CLZ action. Additional glutamate system genes and multiple markers should be investigated. Further studies with greater sample size are required before firm conclusions can be drawn. In addition, it would be helpful to investigate other phenotypes such as cognition and tardive dyskinesia because glutamate neurotransmission also plays a role in these areas.

Project description:BackgroundAntibiotic resistance is an increasing phenomenon in many bacterial pathogens including uropathogenic Escherichia coli. Hypothetical anti-virulent agents could be a solution, but first clear virulence associated gene-pool of antibiotic resistant isolates have to be determined. The aim of this study is to investigate the significant associations between genes encoding VFs with antibiotic resistance and phylogenetic groups in UPEC isolates.ResultsThe majority of 248 UPEC isolates belonged to phylogenetic group B2 (67.3%). The maximum and minimum resistance was attributed to amoxicillin (90.3%) and both fosfomycin and imipenem (1.6%) respectively. 11.3% of isolates were resistant to all antibiotic agents except that of imipenem, nitrofurantoin and fosfomycin. These highly resistant isolates were placed only in group B2 and D. The most prevalent virulence gene was ompA (93.5%). The hlyA was the only virulence gene that was significantly more prevalent in the highly resistant isolates. The ompA, malX and hlyA genes were obviously more abundant in the antibiotic resistant isolates in comparison to susceptible isolates. The papC gene was associated with amoxicillin resistance (p-value = 0.006, odds ratio: 26.00).ConclusionsIncreased resistance to first line drugs prescribed for UTIs were detected in CA-UPEC isolates in our study.. Minimal resistance was observed against nitrofurantoin, fosfomycin and imipenem. Therefore, they are introduced for application in empirical therapy of UTIs. Fosfomycin may be the most effective antibiotic agent against highly resistant UPEC isolates. The presence of the ompA, malX and hlyA genes were significantly associated with resistance to different antibiotic agents. We assume that the ability of UPEC isolates to upgrade their antibiotic resistance capacity may occurs in compliance with the preliminary existence of specific virulence associated genes. But, more investigation with higher number of bacterial isolates, further virulence associated genes and comparison of gene pools from CA-UPEC isolates with HA-UPEC are proposed to confirm these finding and discovering new aspects of this association.

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Variants and expression changes in PPAR-encoding genes display no significant association with schizophrenia.

Publications

Variants and expression changes in PPAR-encoding genes display no significant association with schizophrenia.

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