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

Li, Dawei; Sulovari, Arvis; Cheng, Chao; Zhao, Hongyu; Kranzler, Henry R.; Gelernter, Joel

doi:10.1038/npp.2013.291

Cited by 87 publications

(87 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More than half of the phenotypically linked SNPs and mutations are associated with drug abuse (predominantly alcohol) (http://www.ncbi.nlm.nih.gov/SNP/), which supports a role for GABA A receptors in addiction risk (Anstee et al, 2013;Li et al, 2014). In particular, GABRA6 has been identified as an inheritable locus for developing alcohol dependence (Radel et al, 2005).…”

Section: Gaba a Receptorsmentioning

confidence: 95%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

View full text Add to dashboard Cite

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

show abstract

Section: Gaba a Receptorsmentioning

confidence: 95%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

View full text Add to dashboard Cite

show abstract

“…Another gene cluster GABRG1, GABRA2, GABRA4 and GABRB1 is present on chromosome 4p12 [19,20]. Several genetic studies, including association and genome-wide association studies, implicate various GABA receptor genes as AD susceptibility candidates [21][22][23][24][25][26][27][28][29][30].…”

Section: Journal Of Addiction Research and Therapymentioning

confidence: 99%

“…Among the commonly studied GABA A receptor gene variants associated with substance dependence none have been determined to be functional or pathogenic. A meta-analysis of the variants in the GABAA receptor genes (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12) by Li et al showed GABRG2 rs211014 to be associated with both alcohol and heroin dependence [28]. Previously, Radel et al identified sib-pair linkage of the 5q34 GABAA receptor genes to alcohol dependence in Finns [50].…”

Section: Sno Variablesmentioning

confidence: 99%

“…Li et al [28] reported positive association with GABRG2 rs211014 in a combined meta-analysis on alcohol, opioid and methamphetamine dependence. The discrepancy in results from other association studies is likely due to differences in ethnicity of the population studied; therefore some SNPs important for a particular population may not be a susceptibility factor for another population.…”

Section: Sno Variablesmentioning

confidence: 99%

See 1 more Smart Citation

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Singh¹,

Grover²,

Gupta³

et al. 2017

J Addict Res Ther

View full text Add to dashboard Cite

Alcohol dependence (AD), associated with high mortality and morbidity is caused due to involvement of both environmental and genetic factors. Behavioral effects of alcohol including cognitive impairment, motor incoordination, tolerance and dependence are likely due to its effect on the multiple brain proteins including neurotransmitters. Dysfunction in these neurotransmitter systems may be at the level of enzymes involved in metabolic degradation, or receptors involved in neurotransmission like dopamine, Gamma-amino butyric acid (GABA), serotonin etc. Genetic polymorphisms in these neurotransmitter systems are implicated in conferring susceptibility to AD. Aim:To identify association of single nucleotide polymorphisms (SNPs) in COMT (rs4680 and rs2075507) and GABAA receptor genes (rs13172914 and rs211014) with AD.Method: A total of 100 AD patients diagnosed on the basis of DSM IV criteria from the outpatient clinic of the National Drug Dependence Treatment Centre (NDDTC) of All India Institute of Medical Sciences (AIIMS), and 100 healthy individuals from the general population were recruited. A detailed history including pattern of drug use and demographic details with pedigree information was noted. Genomic DNA from peripheral blood samples was processed for PCR amplification followed by restriction digestion to screen for the presence of polymorphisms. Genotype and allele frequencies were evaluated and correlated with alcohol use parameters including duration of alcohol use, age at onset of alcohol use, quantity of alcohol consumed (gms/day) and WHO ASSIST score and levels of liver function enzymes (SGPT and SGOT). Statistical analysis was performed using SPSS v21.0.Results: Genetic analysis of the study group revealed COMT rs4680 to be significantly associated with AD (p=0.03), while the other COMT SNP rs2075507 showed an association with increased levels of SGPT in the patients. GABAA receptor gene polymorphisms showed no association with AD. Conclusion:The study suggests a role of COMT gene polymorphism rs4680 in conferring susceptibility to AD.

show abstract

“…However, unlike other addictive drugs (eg, morphine, cocaine or nicotine) which have specific molecular targets, EtOH affects much wider neuronal functions including phospholipid membranes, various ion channels and receptors, synaptic and network functions, and intracellular signaling molecules [8] . Although it has been extensively investigated [9] ), the major target mediating EtOH reward signaling and the precise mechanisms of EtOH reward and dependence are still poorly understood [10] . This gap in knowledge results in a therapeutic barrier in the treatment of alcoholism.…”

Section: Introductionmentioning

confidence: 99%

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

Gao

Taylor

2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence. Alcoholism is a serious public health problem and has been identified as the third major cause of preventable mortality in the world. Worldwide, about 2 billion people consume alcohol, with 76.3 million having diagnosable alcohol use disorders. Alcohol is currently responsible for the death of 4% of adults worldwide (about 2.5 million deaths each year), and this number will be significantly increased by 2020 unless effective action is taken. Alcohol is the most commonly abused substance by humans. Ethanol (EtOH) is the intoxicating agent in alcoholic drinks that can lead to abuse and dependence. Although it has been extensively studied, the mechanisms of alcohol reward and dependence are still poorly understood. The major reason is that, unlike other addictive drugs (eg, morphine, cocaine or nicotine) that have specific molecular targets, EtOH affects much wider neuronal functions. These functions include phospholipid membranes, various ion channels and receptors, synaptic and network functions, and intracellular signaling molecules. The major targets in the brain that mediate EtOH's effects remain unclear. This knowledge gap results in a therapeutic barrier in the treatment of alcoholism. Interestingly, alcohol and nicotine are often co-abused, which suggests that neuronal nicotinic acetylcholine receptors (nAChRs), the molecular targets for nicotine, may also contribute to alcohol's abusive properties. Here, we briefly summarize recent lines of evidence showing how EtOH modulates nAChRs in the mesolimbic pathway, which provides a perspective that nAChRs are important targets mediating alcohol abuse.

show abstract

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

Cited by 87 publications

References 69 publications

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

Contact Info

Product

Resources

About