Association of GABRG3 with Alcohol Dependence

Indiana University School of Medicine, Indianapolis, Indiana, USA.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.21). 02/2004; 28(1):4-9. DOI: 10.1097/01.ALC.0000108645.54345.98
Source: PubMed


Evidence from human, animal, and in vitro cell models suggests that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive.
We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes: GABRA5, GABRB3, and GABRG3.
Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes.
These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.

Download full-text


Available from: Alison Goate,
  • Source
    • "Second, GABA receptor genes are among the most promising candidates linked to substance use disorders. The increased risk of nicotine and alcohol phenotypes associated with genetic variants in the GABA system is moderate but sufficiently large to be detectable in regression models (Agrawal et al. 2006; Dick et al. 2006; 2009; Edenberg et al. 2004; Enoch et al. 2010; Philibert et al. 2009), and has been confirmed using meta-analysis (Li et al., 2014). "

    American Journal of Sociology 01/2016; In Press. · 3.17 Impact Factor
  • Source
    • "Cell survival and neuronal growth Learning deficits (Nekrasova et al. 2008) 3 . 8 3 3 0 2 GMDS 20:9816860 rs1013303 CNS development −4.6509652 HK2 6:1749928 rs2229626 Glycolytic metabolism Glioblastoma (Wolf et al. 2011) −4.2077072 COL9A1 2:75113657 rs476863 Protein digestion 3.8077398 COLEC12 6:70927967 rs2076867 Vascular endothelium function −3.7897615 GABRG3 20:9815528 rs9672753 GABA signaling Alcohol/psychostimulant dependence (Dick et al. 2004) "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale Researchers studying behavioral and physiologic effects of d-amphetamine have explored individual response differences to the drug. Concurrently, genome-wide analyses have identified several single-nucleotide polymorphisms (SNPs) associated with these traits. Univariate methods can identify SNPs associated with behavioral and physiological traits, but multivariate analyses allow identification of clusters of related biologically relevant SNPs and behavioral components. Objectives The aim of the study was to identify clusters of related biologically relevant SNPs and behavioral components in the responses of healthy individuals to d-amphetamine using multivariate analysis. Methods Individuals (N = 375) without substance abuse histories completed surveys and detailed cardiovascular monitoring during randomized, blinded sessions: d-amphetamine (10 and 20 mg) and placebo. We applied parallel independent component analysis (Para-ICA) to data previously analyzed with univariate approaches, revealing new associations between genes and behavioral responses to d-amphetamine. Results Three significantly associated (p SNPs in calcium and glutamatergic signaling pathways. The second associated components included the “Anger” items from the Profile of Mood States (POMS) questionnaire and the marijuana effects from the Addiction Research Center Inventory (Cuyas, Verdejo-Garcia et al.), with enriched genetic pathways involved in cardiomyopathy and MAPK signaling. The final pair included “Anxious,” “Fatigue,” and “Confusion” items from the POMS questionnaire, plus functional pathways related to cardiac muscle contraction and cardiomyopathy. Conclusions Multifactorial genetic networks related to calcium signaling, glutamatergic and dopaminergic synapse function, and amphetamine addiction appear to mediate common behavioral and cardiovascular responses to d-amphetamine.
    Psychopharmacology 04/2015; 232(15). DOI:10.1007/s00213-015-3914-1 · 3.88 Impact Factor
  • Source
    • "Linkage and genome-wide association studies (GWASs) have implicated many regions and genes for dependence on alcohol, tobacco, and opiates. GABRA2, CHRM2, ADH4, PKNOX2, GABRG3, TAS2R16, SNCA, OPRK1, and PDYN have all been associated with alcohol dependence with various degrees of replication [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]. Associations of other candidate alcohol dependence genes, such as KIAA0040, ALDH1A1, and MANBA [18, 20, 22–25], remain to be confirmed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Substance dependence is a complex environmental and genetic disorder with significant social and medical concerns. Understanding the etiology of substance dependence is imperative to the development of effective treatment and prevention strategies. To this end, substantial effort has been made to identify genes underlying substance dependence, and in recent years, genome-wide association studies (GWASs) have led to discoveries of numerous genetic variants for complex diseases including substance dependence. Most of the GWAS discoveries were only based on single nucleotide polymorphisms (SNPs) and a single dichotomized outcome. By employing both SNP- and gene-based methods of analysis, we identified a strong (odds ratio = 13.87) and significant (P value = 1.33E - 11) association of an SNP in the NCK2 gene on chromosome 2 with opiates addiction in African-origin men. Codependence analysis also identified a genome-wide significant association between NCK2 and comorbidity of substance dependence (P value = 3.65E - 08) in African-origin men. Furthermore, we observed that the association between the NCK2 gene (P value = 3.12E - 10) and opiates addiction reached the gene-based genome-wide significant level. In summary, our findings provided the first evidence for the involvement of NCK2 in the susceptibility to opiates addiction and further revealed the racial and gender specificities of its impact.
    The Scientific World Journal 02/2013; 2013(4):748979. DOI:10.1155/2013/748979 · 1.73 Impact Factor
Show more