• Effect of Two Nonsynonymous Variants of the GABAergic Enzyme Genes, GAD1 and ALDH5A1, on Processing Speed in Healthy Controls and Schizophrenia Patients

      Whittaker, Clare; Hong, Elliot (2013)
      Schizophrenia has been associated with altered GABAergic function in the brain. Gamma aminobutyric acid (GABA) is synthesized by GAD67 (glutamate decarboxylase weighing 67kDa) and GAD65, encoded in GAD1 and GAD2 genes, respectively, and degraded by succinic semialdehyde dehydrogenase (SSADH) encoded in ALDH5A1. Previous research suggests that individuals with schizophrenia have an elevated level of GABA and also have a processing speed deficit. We hypothesized that the GAD1 variant, Arg532Gln, and the ALDH5A1 variant, His180Tyr, could alter these enzymes' functions and be associated with the processing speed deficit seen in individuals with schizophrenia. The ALDH5A1 variant His180Tyr is known to reduce the enzyme function of SSADH; while the effect of the GAD1 variant, Arg532Gln is currently unknown. The Digit Symbol coding task was used to measure processing speed in 153 healthy controls and 158 patients with schizophrenia. Both groups were genotyped for GAD1 Arg532Gln and ALDH5A1 His180Tyr missense SNPs. Using this clinical information, we attempted to determine the amount of variation in Digit Symbol coding score between patients and controls that could be explained by these GAD1 and ALDH5A1 SNPs. Case-control analysis was also performed to determine if either SNP was associated with a diagnosis of schizophrenia. A GAD67 functional enzyme assay was developed to determine if Arg532Gln is a functional mutation and therefore partially responsible for the processing speed deficit present in many individuals with schizophrenia. Results showed that GAD1 Arg532Gln was significantly associated with reduced digit symbol score in the control group (R2=4.9%, p=0.006) and the schizophrenic group (R2=3.7%, p=0.015); however, only the association with the control population remained significant after the Bonferroni correction. The functional GAD67 enzyme assay showed that Arg532Gln results in increased GABA production. ALDH5A1 His180Tyr was also significantly associated with reduced digit symbol score in the control group (R2=5.6%, p=0.003), but not the schizophrenic group (R2=1.5%, p=0.131). Neither SNP was associated with schizophrenia in either the Caucasian or African American population. In conclusion, the GAD1 and ALDH5A1 variants are not significantly associated with schizophrenia, but are significantly associated with processing speed. We also found that Arg532Gln results in increased GAD67 activity.