Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in...

Area of Science:

• Neurogenetics
• Molecular Psychiatry
• Mitochondrial Biology

Background:

• Schizophrenia is associated with cognitive deficits, and a previous study linked the 6p25-p24 chromosomal region to high composite cognitive deficit (CD) scores.
• Association mapping identified a 260 kb region within 6p25-p24 containing genes LYRM4 and FARS2, which are significantly associated with CD scores and memory performance.

Purpose of the Study:

• To identify the functional genetic variants within the 6p25-p24 region associated with cognitive deficits in schizophrenia.
• To investigate the impact of these variants on LYRM4 gene expression and its potential role in schizophrenia pathogenesis.

Main Methods:

• Association mapping and sequencing of a 260 kb region, focusing on single-nucleotide polymorphisms (SNPs) in the LYRM4 and FARS2 promoter regions.
• Luciferase reporter assays, lymphoblast expression analysis, gel-shift assays, and DNA breathing dynamics modeling to determine functional variants and their effects.
• Analysis of SNP associations with composite cognitive deficit (CD) scores and memory performance.

Main Results:

• A cluster of 22 SNPs in tight linkage disequilibrium was identified in the overlapping promoter region of LYRM4 and FARS2.
• Luciferase assays showed that a haplotype of promoter SNPs (rs7752203-rs4141761) with C-G alleles was associated with higher LYRM4 expression and nuclear protein binding.
• Conversely, the G-A allele combination of these SNPs was linked to reduced LYRM4 expression, poor memory, and high CD scores.

Conclusions:

• The promoter variants rs7752203 and rs4141761 in LYRM4 are functional, influencing gene expression and cognitive performance in schizophrenia.
• LYRM4 downregulation may contribute to schizophrenia pathogenesis through impaired mitochondrial function and oxidative stress.
• These findings highlight the role of mitochondrial gene regulation in schizophrenia-related cognitive deficits.