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Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression
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Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression
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Journal Article
Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression
2007
Overview
Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD
67
), encoded by
GAD1
, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-
O
-methyltransferase (
COMT
) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in
GAD1
influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5′ flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5′ untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of
GAD1
mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in
COMT
and SNPs in
GAD1
, suggesting a potential biological synergism leading to increased risk. These coincident results implicate
GAD1
in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adult
/ Adult and adolescent clinical studies
/ Alleles
/ Biological and medical sciences
/ Catechol
/ Catechol O-methyltransferase
/ Catechol O-Methyltransferase - genetics
/ Cerebral Cortex - blood supply
/ Cerebral Cortex - physiopathology
/ Enzymes
/ Etiology
/ Female
/ Functional magnetic resonance imaging
/ GABA
/ Gene Expression - physiology
/ Genetic Predisposition to Disease
/ Genomes
/ Glutamate Decarboxylase - genetics
/ Humans
/ Image Processing, Computer-Assisted - methods
/ Magnetic Resonance Imaging - methods
/ Male
/ Medicine
/ Memory
/ Polymorphism, Single Nucleotide
/ Proteins
/ Psychology. Psychoanalysis. Psychiatry
/ Schizophrenia - physiopathology
