Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• The DISC1 gene is linked to schizophrenia susceptibility.
• Risk SNPs suggest DISC1 impacts hippocampal structure and function.
• Altered DISC1 pathway gene expression may explain its pathogenic role.

Purpose of the Study:

• To investigate the expression of DISC1 and its partners (NUDEL, FEZ1, LIS1) in postmortem brain tissue from schizophrenia patients and controls.
• To determine if DISC1 expression or its binding partners' expression is altered in schizophrenia.
• To associate DISC1 pathway gene expression with DISC1 risk polymorphisms.

Main Methods:

• Postmortem human brain tissue analysis (hippocampus and dorsolateral prefrontal cortex).
• Quantitative analysis of DISC1, NUDEL, FEZ1, and LIS1 mRNA expression.
• Association study of gene expression with DISC1 single nucleotide polymorphisms (SNPs).

Main Results:

• No significant difference in DISC1 mRNA expression was found in schizophrenia patients.
• Expression of NUDEL, FEZ1, and LIS1 was significantly reduced in schizophrenic subjects.
• Reduced expression of NUDEL, FEZ1, and LIS1 was associated with high-risk DISC1 polymorphisms.

Conclusions:

• These findings suggest that abnormalities in the DISC1 molecular pathway, specifically reduced expression of its partners, are involved in schizophrenia pathophysiology.
• The genetic association of schizophrenia with DISC1 may be mediated by altered expression of its binding partners.
• Further research into the DISC1 pathway is warranted for understanding schizophrenia etiology.