Mutation screen of the GAD2 gene and association study of alcoholism in three populations

Abstract

Synaptic actions of gamma-amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism. We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD). We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals. Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls. These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G. These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009). We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310). Analyses in these populations did not support a role for GAD2 in alcoholism. In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs. The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.

Polymorphisms in the GAD2 gene‐region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders

“…As mentioned above, our results are in line with previous genetic studies reporting associations of polymorphism in the GAD2 locus with BI [Smoller et al, 2001] and alcohol dependence [Lappalainen et al, 2007], for which increased anxiety is a risk factor [Cosci et al, 2007;Cowley 1992]. As an explanatory mechanism for the high degree of comorbidity between alcoholism and both AD and MD [Kessler et al, 2005[Kessler et al, , 1997, alcohol as a self medication has been referred to [Allan 1995;Kushner et al, 2000].…”

“…The polymorphism associated with BI (rs3138541, chr10:26547409-26547576) [Smoller et al, 2001] and with severe alcoholism (rs2236418, chr10:26545502) [Lappalainen et al, 2007], are closest to rs2839670 genotyped in our study and 3.1 or 1.2 kb downstream of this polymorphism, respectively. Rs2839670 lies 5 0 of GAD2, a region that has been proposed as a promotor-site for this gene [Edelhoff et al, 1993;Bu and Tobin, 1994].…”

“…The so far largest association study of polymorphisms within both GAD1 and GAD2 analyzing 1,128 subjects, did not find evidence for associations of GAD2 with neuroticism, anxiety disorders (AD) or major depression (MD) [Hettema et al, 2006]. A recent study described a significant association of a GAD2-polymorphism with alcohol dependence in Russian samples but this association could not be replicated in a European American sample [Lappalainen et al, 2007].…”

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

“…GAD2 (glutamic acid decarboxylase 2), a possible candidate in this region, has been putatively implicated, although not unequivocally, for its role in acute ethanol consumption and withdrawal, in animal models (Fehr et al, 2003). Two recent association studies in humans, however report negative findings for the role of GAD2 in the risk for alcoholism while another found limited evidence for the role of this gene in association with anxiety disorders, depression and neuroticism (Hettema et al, 2006;Lappalainen et al, 2007;Loh et al, 2006). A smaller linkage peak at 90-110 cM encompasses candidate genes such as HTR7 (5-Hydroxytryptamine receptor 2B) and VMAT2 (vesicular monoamine oxidase 2), as well as KCNMA1 (calcium activated channel).…”

Disease-driven detection of differential inherited SNP modules from SNP network

“…Although many susceptive genes have been identified by research of the genome, transcriptome and proteome (Belfer et al, 2007;Lappalainen et al, 2007;Liu et al, 2005), further genomewide detection of disease risk SNPs is necessary to understand its aetiology more fully. Applying the disease-driven method to the alcoholism data, at the threshold of c as twice the mean distance, 96.45% SNPs were included in the SNP network, 548 significant SNP modules (including 784 individual SNPs, the modules are designated by the module number; if SNPs are located in more than one gene or no gene, those modules are named by the corresponding gene symbols, see details in Table S11) were identified.…”