Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia

Abstract

Recent evidence from postmortem studies suggests that GAD1 encoding the gamma-aminobutyric acid (GABA) synthetic enzyme GAD67 is a functional candidate susceptibility gene for both bipolar affective disorder (BPAD) and schizophrenia. Previous studies suggest linkage between D2S326 near GAD1 and BPAD. We systematically screened GAD1 exons, flanking intronic sequences, and the promoter sequence for polymorphisms in 16 BPAD patients and five controls from Denmark. We identified eight single nucleotide polymorphisms (SNPs) including two in the promoter sequence. An association study of SNPs covering GAD1 was performed in a Danish sample of 82 BPAD subjects and 120 controls and in a Scottish sample of 197 individuals with schizophrenia, 200 BPAD subjects and 199 controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated from genotype data from eight SNPs. Strong pairwise LD was observed among all pairs of neighboring markers. In the Danish sample, we found weak association between BPAD and two promoter SNPs spaced 1 kb apart. Furthermore, one, two, and three loci haplotype analysis showed weak association with BPAD in the Danish sample. The results from the association studies indicate that promoter variants are of importance for the Danish BPAD cases and we cannot reject the hypothesis of GAD1 as a functional candidate gene for BPAD. No association was observed between BPAD or schizophrenia and any of the investigated SNPs in the Scottish sample set. Thus the results obtained from the Scottish sample suggest that the GAD1 gene variants do not play a major role in the predisposition to schizophrenia.

Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism

“…Using three SNPs different from those in the current study, they found no significant allele frequency differences between their cases and controls. A second group 34 that examined GAD1 did so in a study of bipolar disorder and schizophrenia using eight SNPs (again, different from those in the current study). They reported 'weak association' for two promoter SNPs in their Danish sample of 82 bipolar cases and 120 controls not replicated in their Scottish sample of 200 bipolar cases and 199 controls.…”

“…32 Among mood disorder phenotypes, while one study found no evidence of association between GAD1 and unipolar depression, 33 a second study reported weak association of this gene with bipolar disorder. 34 The aims of the present study are two-fold: (1) use the genetic information inherent in a large, population-based twin sample phenotyped for a broad range of related psychiatric phenotypes to select a powerful case-control sample for candidate gene association studies, and (2) apply this method to investigate possible association of the GAD1 and GAD2 genes with genetic risk shared between major depressive disorder, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and N.…”

Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters

“…Interestingly, treatment with the atypical antipsychotic, clozapine, resulted in increased Mll1 occupancy and H3K4me3 levels at the Gad1/GAD1 promoter. Finally, we demonstrate that schizophrenia subjects biallelic for GAD1 haplotypes previously associated with schizophrenia and mood and anxiety disorders (Addington et al, 2005;Lundorf et al, 2005;Hettema et al, 2006;Straub et al, 2007) were affected by a deficit in prefrontal GAD1 mRNA, in conjunction with a shift from open (H3K4me3) toward repressive (H3K27me3) chromatin-associated histone methylation. These novel findings present the first evidence that MLL1-mediated histone lysine methylation is an important regulator of GABAergic chromatin structures that are dynamically regulated throughout an extended period of human PFC development and involved in the pathophysiology of chronic psychotic illness, including schizophrenia.…”

“…Several GAD1 SNPs confer genetic risk for increased rate of frontal lobe gray matter loss, in conjunction with childhood onset and other types of schizophrenia (Addington et al, 2005;Straub et al, 2007), and bipolar illness (Lundorf et al, 2005). Given the proximity of these SNPs to the TSS of GAD1 (Fig.…”

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

“…A case-control study of association with schizophrenia using a single SNP (rs769404, marker M13 in this study) was negative. 62 A second study 63 reported case-control results for a Danish bipolar affective disorder (BPAD) sample and Scottish BPAD and schizophrenia samples for eight SNPs, six of which we tested here (M03, M04, M09, M13, M16 and M19 in Table 1). They found no P-values < 0.05 in the Scottish schizophrenia or BPAD samples, and in the Danish BPAD sample found genotype-wise P-values of 0.062, 0.016 and 0.096 for SNPs M03, M04 and M09, respectively.…”