GABAA receptor polymorphisms in alcohol use disorder in the GWAS era

  title={GABAA receptor polymorphisms in alcohol use disorder in the GWAS era},
  author={Mairi Koulentaki and Elias Kouroumalis},
Alcohol use disorder (AUD) is a chronic, relapsing, neuro-psychiatric illness of high prevalence and with a serious public health impact worldwide. It is complex and polygenic, with a heritability of about 50%, and influenced by environmental causal heterogeneity. Risk factors associated with its etiology have a genetic component. GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in mammalian brain. GABAA receptors are believed to mediate some of the physiological and behavioral… 

Effects of Common and Rare Chromosome 4 GABAergic Gene Variation on Alcohol Use and Antisocial Behavior.

It is suggested that both rare and common variant associations in GABRA2 confer risk for alcohol use disorder and antisocial behaviors, indicating a potential liability toward externalizing behavior more broadly.

Substance Dependence: Overview of the Environmental, Genetic, Epigenetic, and Imaging Studies

Brain imaging techniques like positron emission tomography/single-photon emission computed tomography can be helpful in the identification of neuroadaptive and neurodegenerative changes which in the future may help in the development of pharmacological treatment targets for SD.

Targeting prefrontal cortex GABAergic microcircuits for the treatment of alcohol use disorder

It is suggested that changes in fast transmission through PFC inhibitory microcircuits are a central component of the neurobiological effects of ethanol and the core symptoms of AUDs.

Novel molecular targets for treating alcohol use disorder and hepatotoxicity

The value of incorporating regulatory information and drug-protein interaction data to highlight promising molecular targets and drugs for treating AUD and ALD is demonstrated.

Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo

Novel information is provided supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo.

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity.

This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight additional molecular targets and drug repurposing candidates for treating AUD and ALD.

Gut microbiota dysbiosis: The potential mechanisms by which alcohol disrupts gut and brain functions

A potential intervention for alcohol addiction through fecal microbiota transplantation, which could normalize the disruption of gut microbiota after AUD, is proposed.

Alcohol-Related Central Nervous System Disorders Associated with Vitamin B Deficiency

It is hypothesized that Cytokine-mediated cytotoxic edema is a pathophysiological mechanism in Marchiafava–Bignami disease, in addition to vitamin B1 deficiency–related mechanisms, which may be useful for disease management in the future.

α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials

Anatomical and electrophysiological evidence indicates that α6-containing GABAA receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

Findings suggest sex differences and GABAAR subunit specificity in alcohol intake in male and female binge-like drinking in a critical area of mesolimbic circuitry—the ventral tegmental area (VTA).



Allelic and haplotypic association of GABRA2 with alcohol dependence

Ten single nucleotide polymorphisms spanning the coding region of this gene were examined in samples of European American subjects with alcohol dependence, and controls screened to exclude substance use disorders, which underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence.

Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

Findings from this extensive meta-analysis of five GABAA receptor genes and substance abuse support their involvement (with the best evidence for GABRA2) in the pathogenesis of AD.

GABRA2 and alcohol use disorders: no evidence of an association in an Italian case-control study.

10 single nucleotide polymorphisms of the 3'-GABRA2 gene, previously reported to be implicated in alcohol dependence, were used to evaluate the linkage between selected SNPs and AUDs in an Italian sample and to compare findings with those of previous studies.

Overview of the Genetics of Alcohol Use Disorder.

The most promising results associated with AUD and alcohol-related phenotypes have included SNPs of the alcohol metabolism genes ADH and ALDH, which have been found to be protective against the development of AUD.

Association of GABRG3 with alcohol dependence.

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 is supported.

Gamma-aminobutyric acid system genes--no evidence for a role in alcohol use and abuse in a community-based sample.

The results suggest that the relationship between alcohol use and GABA system genes may be limited to particular contexts, such as when accompanied by polysubstance abuse or a familial history of alcoholism.

Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.

The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABra2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.

Association of GABAA receptors and alcohol dependence and the effects of genetic imprinting

  • Jiuzhou Z. SongDaniel L. Koller H. Edenberg
  • Medicine
    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
  • 2003
Consistent, although weak, linkage disequilibrium between GABRB1 (located on chromosome 4) and alcoholism is found and these data are consistent with an association between the expressed alleles in the GABAA‐gene cluster on chromosome 15 and alcoholism that is modulated by genetic imprinting.