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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Peroxisome proliferator-activated receptors (PPARs) have been implicated in the etiology of schizophrenia (SCZ).
• The direct association between genetic variants in PPAR-encoding genes and SCZ remains unclear.
• PPARA, PPARD, and PPARG are key genes involved in various cellular processes.

Purpose of the Study:

• To investigate the potential linkage between SCZ and genetic variants in PPARA, PPARD, and PPARG.
• To analyze the expression levels of these PPAR genes in human brain regions and in early-onset SCZ patients.
• To explore the specific role of PPARs in early-onset SCZ phenotypes, particularly in females.

Main Methods:

• Genome-wide association study (GWAS) to test for SCZ association with PPAR variants.
• Mega-analysis of 14 gene expression profiling datasets across human brain regions.
• Quantification of PPARA, PPARD, and PPARG expression in early-onset SCZ patients' whole blood.

Main Results:

• Only one PPARG polymorphism (rs62242085) showed a minor frequency deviation in the SCZ cohort (P=0.035).
• No significant expression changes were observed for PPAR genes in various brain regions or in overall early-onset SCZ patients' blood (P>0.14 and P>0.22, respectively).
• Female early-onset SCZ patients exhibited significantly decreased PPARD expression (LFC=-0.55, P=0.02) and a non-significant decrease in PPARG expression (LFC=-1.30, P=0.13) compared to controls.

Conclusions:

• The study does not support a significant association between PPAR-encoding gene variants and SCZ.
• PPARD and PPARG warrant further investigation for their roles in early-onset SCZ, especially within female populations.
• PPAR gene expression may be altered in specific subgroups of SCZ patients, suggesting potential sex-specific mechanisms.