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Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia.
Joseph H Callicott1, Richard E Straub, Lukas Pezawas
1Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, Division of Intramural Research, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. callicottj@mail.nih.gov
Summary
Disrupted-in-schizophrenia 1 (DISC1) gene variations are linked to schizophrenia risk. The Ser704Cys variant impacts hippocampal structure and function, suggesting a mechanism for DISC1
Area of Science:
- Neurogenetics
- Psychiatric Genetics
- Molecular Psychiatry
Background:
- Disrupted-in-schizophrenia 1 (DISC1) is a key candidate gene for schizophrenia.
- DISC1 is primarily expressed in the hippocampus, a brain region crucial for cognitive function.
Purpose of the Study:
- To investigate the association between DISC1 genetic variations and schizophrenia.
- To explore the impact of DISC1 allelic variation on hippocampal structure and function.
Main Methods:
- Genotyping of 12 single-nucleotide polymorphisms (SNPs) across the DISC1 gene.
- Family-based association study to analyze SNP and haplotype associations with schizophrenia.
- Functional magnetic resonance imaging (fMRI) and volumetric analysis to assess hippocampal phenotypes in healthy subjects.
Main Results:
- A specific three-SNP haplotype and the Ser704Cys SNP within DISC1 were significantly associated with schizophrenia.
- The Ser allele of DISC1 Ser704Cys was linked to reduced hippocampal gray matter volume in healthy individuals.
- Altered hippocampal engagement during cognitive tasks was observed in healthy subjects carrying the Ser allele.
Conclusions:
- Allelic variations in DISC1, particularly the Ser704Cys SNP and associated haplotypes, confer risk for schizophrenia.
- The mechanism underlying DISC1's influence on schizophrenia likely involves structural and functional changes in the hippocampus.