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.

Keywords: bioinformatics; peroxisome proliferator-activated receptors; psychotic disorders.

Figure 1. Boxplot of the FDR corrected P-values for the SNPs located within each PPAR-encoding locus

The original P-values of the SNPs were extracted from the combined analysis of two large-scale GWAS data [18].

Figure 2. The effect size, 95% confidence interval, and weights for expression levels of genes encoding (A) PPAR-α; (B) PPAR-δ; (C) PPAR-γ

The bar plot on the right of each figure represents the normalized weights for each dataset/study, ranged within (0, 1); the brighter (green) the color, the larger the weight (labeled right next to the bar). The star (in red) and lines (in blue) on the left are the mean of effect size (log fold change) and 95% confidence interval (CI) of each dataset/study, respectively.

Figure 3. The expression levels of PPAR encoding genes in PNMCs collected from early onset SCZ patients and healthy controls

EOS: early-onset schizophrenia group. HC: healthy control group. (A) Comparison results from Female EOS vs. Female HC. (B) Comparison results from Male EOS vs. Male HC. (C) Comparison results from All EOS vs. All HC.