Allelic and haplotypic association of GABRA2 with alcohol dependence

Covault, Jonathan; Gelernter, Joel; Hesselbrock, Victor; Nellissery, Maggie; Kranzler, Henry R.

doi:10.1002/ajmg.b.30091

Cited by 273Genetic Associations and EpidemiologySubstance Abuse Treatment and OutcomesNeurotransmitter Receptor Influence on Behavior

Allelic and haplotypic association of GABRA2 with alcohol dependence

Covault, Jonathan, Gelernter, Joel, Hesselbrock, Victor, Nellissery, Maggie, Kranzler, Henry R.·2004·American Journal of Medical Genetics Part B Neuropsychiatric Genetics

DOI 10.1002/ajmg.b.30091

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Abstract

Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABAA neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA-related proteins are functional candidates to influence risk of alcohol dependence. Two genome-wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABAA receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABAA receptor alpha-2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 bp in the middle and 3'-portion of the GABRA2 gene (range of P-values = 0.008-0.03). When the subset of the alcohol-dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P-values = 0.002-0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol-dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co-morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence.

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Human genetics studies have noted associations between GABAAR genes and different aspects of alcoholism.
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Result
Genomewide Linkage Scan for Opioid Dependence and Related Traits
Gelernter, J. E., Panhuysen, C. I. M., Wilcox, M., HESSELBROCK, V. M., Rounsaville, B. J., Poling, J. C., Weiss, R. D., Sonne, S. C., Zhao, H., Farrer, L. A., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/503631 · Cited by 129 · see citing works
GABAA receptors and their associated proteins: Implications in the etiology and treatment of schizophrenia and related disorders
Charych, E. I., Liu, F., Moss, S. J., & Brandon, N. J. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.07.027 · Cited by 127 · see citing works
“It might also be argued that these changes in α2 subunit expression are related to comorbid substance abuse since 1) numerous reports have demonstrated that genetic variation in the gene encoding the α2 subunit is strongly associated with risk for alcoholism (Covault et al., 2004; Covault et al., 2008; Dick et al., 20…”
Background
Approach to the genetics of alcoholism: A review based on pathophysiology
Köhnke, M. D. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.06.021 · Cited by 124 · see citing works
Genetics of human brain oscillations
Begleiter, H., & Bernice Porjesz, A. (2006) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2005.12.013 · Cited by 123 · see citing works
“…that the same GABAA receptor gene (GABRA2) associated with the beta frequency of the EEG is also associated with a DSM-IV diagnosis of alcohol dependence (Edenberg et al., 2004), a finding that has been replicated in several recent independent studies (Covault et al., 2004; Xu et al., 2004).”
Result
Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men
Baik, I., Cho, N. H., Kim, S. H., Han, B.-G., & Shin, C. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001776 · Cited by 119 · see citing works
Genetics of alcohol dependence
Gelernter, J. E., & Kranzler, H. R. (2009) · Human Genetics · doi:10.1007/s00439-009-0701-2 · Cited by 118 · see citing works
“…several alcohol metabolizing enzymes, there are now several other genes that can be regarded as conWrmed risk loci (GABRA2; Edenberg et al. 2004; Covault et al. 2004; Lappalainen et al. 2005; Fehr et al. 2006), or strong candidates based on published data (e.g., CHRM2, Wang et al. 2004; Luo et…”
The Genetics of Substance Dependence
Wang, J.-C., Kapoor, M., & Goate, A. (2012) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-090711-163844 · Cited by 117 · see citing works
“Several subsequent studies using case-control samples replicated the association between GABRA2 and alcohol dependence, though the nature of the association and the specific variants associated with alcohol dependence differ in some samples (27, 40, 43, 80, 118).”
Practical population group assignment with selected informative markers: Characteristics and properties of Bayesian clustering via STRUCTURE
Yang, B., Zhao, H., Kranzler, H. R., & Gelernter, J. E. (2005) · Genetic Epidemiology · doi:10.1002/gepi.20070 · Cited by 111 · see citing works
“(We have exploited this unusual property of FY to approximate admixture potential in three previous studies [Lappalainen et al., 2002; Luo et al., 2004; Covault et al., 2004].)”
Association Between Val66Met Brain‐Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post‐Treatment Relapse in Alcohol Dependence
Wojnar, M., Brower, K. J., Strobbe, S., Ilgen, M., Matsumoto, H., Nowosad, I., Sliwerska, E., & Burmeister, M. (2009) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00886.x · Cited by 125 · see citing works
“A number of biological markers, including genetic polymorphisms, have been associated with a predisposition to develop alcohol dependence (Covault et al., 2004; Edenberg, 2007; Edenberg and Foroud, 2006; Edenberg and Kranzler, 2005; Gscheidel et al., 2000).”
Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism
Enoch, M., Schwartz, L., Albaugh, B., Virkkunen, M. E., & Goldman, D. A. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30336 · Cited by 107 · see citing works
“Three earlier studies have found an association with alcoholism in the sameGABRA2 haplotype block that is distal to intron 3 [Covault et al., 2004; Edenberg et al., 2004; Lappalainen et al., 2005].”
BackgroundMethodResultInfluential
Marital status, alcohol dependence, and GABRA2: evidence for gene-environment correlation and interaction.
Dick, D. M., Arpana Agrawal, A., Schuckit, M. A., Bierut, L. J., Hinrichs, A. L., Fox, L. W., Mullaney, J., Cloninger, C. R., HESSELBROCK, V. M., Nürnberger, J. I., et al. (2006) · Journal of Studies on Alcohol · doi:10.15288/jsa.2006.67.185 · Cited by 106 · see citing works
Alcohol Use Disorder: Neurobiology and Therapeutics
Yang, W., Singla, R., Maheshwari, O., Fontaine, C. J., & Gil‐Mohapel, J. (2022) · Biomedicines · doi:10.3390/biomedicines10051192 · Cited by 111 · see citing works
Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder
Li, D., Sulovari, A., Cheng, C., Zhao, H., Kranzler, H. R., & Gelernter, J. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.291 · Cited by 103 · see citing works
“In the end, 27 studies (Chang et al, 2002; Covault et al, 2004, 2008; Enoch et al, 2009; Fehr et al, 2006; Foley et al, 2004; Han et al, 2008; Hsu et al, 1998; Lappalainen et al, 2005; Li et al, 2002; Lin et al, 2003; Loh et al, 1999, 2000, 2007; Lydall et al, 2011; Nishiyama et al, 2005; Onori et…”
GABRG1 and GABRA2 as Independent Predictors for Alcoholism in Two Populations
Enoch, M., Hodgkinson, C. A., Yuan, Q., Albaugh, B., Virkkunen, M. E., & Goldman, D. A. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.171 · Cited by 100 · see citing works
“…been with two common yin-yang haplotypes within the haplotype block that extends downstream from intron 3 in the direction of the adjacent GABRG1 gene (Agrawal et al, 2006; Covault et al, 2004; Edenberg et al, 2004; Enoch et al, 2006a; Fehr et al, 2006; Lappalainen et al, 2005; Soyka et al, 2008).”
Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach
Rodd, Z. A., Bertsch, B. A., Strother, W. N., Le-Niculescu, H., Balaraman, Y., Hayden, E. P., Jerome, R. E., Lumeng, L., Nürnberger, J. I., Edenberg, H. J., et al. (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500420 · Cited by 95 · see citing works
Neuroimaging Risk Markers for Substance Abuse: Recent Findings on Inhibitory Control and Reward System Functioning
Heitzeg, M. M., Cope, L. M., Martz, M. E., & Hardee, J. E. (2015) · Current Addiction Reports · doi:10.1007/s40429-015-0048-9 · Cited by 97 · see citing works
Neurophysiological Endophenotypes, CNS Disinhibition, and Risk for Alcohol Dependence and Related Disorders
Bernice Porjesz, A., & Rangaswamy, M. (2007) · The Scientific World JOURNAL · doi:10.1100/tsw.2007.203 · Cited by 94 · see citing works
“The association between GABRA2 and alcohol dependence has been replicated by a number of groups throughout the world[23,24,25,26].”
Background
Genomewide suggestive linkage of opioid dependence to chromosome 14q
Lachman, H. M., Fann, C. S. J., Bartzis, M. I., Evgrafov, O. V., Rosenthal, R. N., Nunes, E. V., Miner, C. R., Santana, M., Gaffney, J., Riddick, A., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm081 · Cited by 92 · see citing works
“Eventually, Edenberg et al. narrowed the search using linkage disequilibrium (LD) mapping and identified SNPs and SNP haplotypes in the GABRA2 gene that were significantly association with alcoholism, a finding that was replicated by Covault et al. (31, 32 ).”
The genetics of alcohol and other drug dependence.
Dick, D. M., & Arpana Agrawal, A. (2008) · Europe PMC (PubMed Central) · Cited by 95 · see citing works
Understanding alcohol use disorders with neuroelectrophysiology
Rangaswamy, M., & Porjesz, B. (2014) · Handbook of clinical neurology · doi:10.1016/b978-0-444-62619-6.00023-9 · Cited by 95 · see citing works
“, 2004), a finding that has been replicated (Covault et al., 2004) and expanded to include other substance dependence in adults and conduct disorder in adolescents (Agrawal et al.”
Markers in the 5′-Region of GABRG1 Associate to Alcohol Dependence and are in Linkage Disequilibrium with Markers in the Adjacent GABRA2 Gene
Covault, J., Gelernter, J. E., Jensen, K. P., Anton, R. F., & Kranzler, H. R. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301456 · Cited by 92 · see citing works
“G (ending in GABRA2 intron 3), which we had previously identified as being in high LD with one another (Covault et al, 2004).”
Influential
GABAA receptor subtype involvement in addictive behaviour
Stephens, D. N., King, S. L., Lambert, J. J., Belelli, D., & Duka, T. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12321 · Cited by 92 · see citing works
“…shows rs279871 to be in 100% linkage disequilibrium with rs279858, the common risk SNP recognized across multiple studies of addicted populations (Covault et al. 2004; Fehr et al. 2006; Lappalainen et al. 2005) and cocaine abuse (Enoch et al. 2010), as well as childhood conduct disorder (Dick et…”
BackgroundResult
Common single nucleotide variants underlying drug addiction: more than a decade of research
Bühler, K., Giné, E., Echeverry‐Alzate, V., Calleja‐Conde, J., de Fonseca, F. R., & López‐Moreno, J. A. (2015) · Addiction Biology · doi:10.1111/adb.12204 · Cited by 88 · see citing works
“This SNP leads to a synonymous A to G nucleotide substitution at position 132 in exon 5 of the gene and was also associated with alcohol dependence by Edenberg et al. (2004) and Covault et al. (2004).”
BackgroundResult
Association of Alcohol Craving With α‐Synuclein (SNCA)
Foroud, T., Wetherill, L. F., Liang, T., Dick, D. M., HESSELBROCK, V. M., Kramer, J., Nürnberger, J. I., Schuckit, M. A., Carr, L. G., Bernice Porjesz, A., et al. (2007) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2007.00337.x · Cited by 89 · see citing works
“…studies have now replicated the initial reports by the Collaborative Study on the Genetics of Alcoholism (COGA) of a role for variation in GABRA2 (Covault et al., 2004; Edenberg et al., 2004; Fehr et al., 2006; Lappalainen et al., 2005), ADH4 (Edenberg et al., 2006; Guindalini et al., 2005; Luo…”
Result
Guidelines for biological treatment of substance use and related disorders, part 1: Alcoholism, first revision
Soyka, M., Kranzler, H. R., HESSELBROCK, V. M., Kasper, S. F., Mutschler, J., Möller, H., & The WFSBP Task Force on Treatment Guidelines for Substance Use Disorders (2016) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2016.1246752 · Cited by 86 · see citing works
“Recent genetic studies also show that vulnerability to alcoholism may be mediated in part through variation in the genes encoding GABA receptor subunits (Covault et al. 2004; Dick et al. 2004; Edenberg et al. 2004; Lappalainen et al. 2005; Fehr et al. 2006; Soyka et al. 2008b).”
Background
Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence
Wetherill, L., Schuckit, M. A., Hesselbrock, V., Xuei, X., Liang, T., Dick, D. M., Kramer, J., Nurnberger Jr., J. I., Tischfield, J. A., Porjesz, B., et al. (2008) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00790.x · Cited by 83 · see citing works
“Recent human studies have identified several genes associated with alcohol dependence, including GABRA2 (Covault et al., 2004; Edenberg et al., 2004; Fehr et al., 2006; Lappalainen et al., 2005), ADH4 (Edenberg et al., 2006; Guindalini et al., 2005; Luo et al., 2005b), GABRG3 (Dick et al., 2004),…”
Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions
Drgon, T., D'Addario, C., & Uhl, G. R. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30349 · Cited by 82 · see citing works
“…encode the alpha 2, alpha 4, beta 1, and gamma 1 receptor subunits for the principal brain inhibitory neurotransmitter, gaminobutyric acid (GABA) [Covault et al. (2004); Am J Med Genet Part B 129B:104–109; Edenberg et al. (2004); Am J Hum Genet 74(4):705–714; Lappalainen et al. (2005); Alcohol…”
BackgroundMethodResultInfluential
Variation in GABRA2 Predicts Drinking Behavior in Project MATCH Subjects
Bauer, L. O., Covault, J., Harel, O., Das, S., Gelernter, J., Anton, R., & Kranzler, H. R. (2007) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2007.00517.x · Cited by 81 · see citing works
“GABRA2 has, for example, been associated with risk for alcohol dependence in six independent studies (Covault et al., 2004; Edenberg et al., 2004; Enoch et al., 2006; Fehr et al., 2006; Lappalainen et al., 2005; Soyka et al., 2007).”
Influential
Polygenic Scores Predict Alcohol Problems in an Independent Sample and Show Moderation by the Environment
Salvatore, J. E., Alıev, F., Edwards, A. C., Evans, D. M., Macleod, J., Hickman, M., Lewis, G., Kendler, K. S., Loukola, A., Korhonen, T., et al. (2014) · Genes · doi:10.3390/genes5020330 · Cited by 81 · see citing works
“In another example, independent groups have found evidence that the α2 encoding subunit of the GABA-A receptor (GABRA2) is associated with alcohol dependence [16,17].”
Background
Review: HPA‐axis activity in alcoholism: examples for a gene–environment interaction
Clarke, T., Treutlein, J., Zimmermann, U. S., Kiefer, F., Skowronek, M. H., Rietschel, M., Mann, K., & Schumann, G. (2008) · Addiction Biology · doi:10.1111/j.1369-1600.2007.00084.x · Cited by 80 · see citing works
“Covault et al. (2004) found that the same previously associated region of GABRA2 (Edenberg et al. 2004) was associated with alcoholism dependence in European American subjects with alcohol dependence.”
Background
Chronic alcoholism: Insights from neurophysiology
Campanella, S., Petit, G., Maurage, P., Kornreich, C., Verbanck, P., & Noël, X. (2009) · Neurophysiologie Clinique · doi:10.1016/j.neucli.2009.08.002 · Cited by 78 · see citing works
“Several studies also reported a very strong association of the same GABRA2 receptor gene (GABA A receptor, alpha 2) with both alcohol dependence and the beta frequency [36,25,175].”
Background
GABAA receptor subtypes and benzodiazepine use, misuse, and abuse
Engin, E. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1060949 · Cited by 79 · see citing works
Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABA A receptors
Dixon, C. I., Morris, H. V., Breen, G., Desrivieres, S., Jugurnauth, S., Steiner, R. C., Vallada, H., Guindalini, C., Laranjeira, R., Messas, G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910117107 · Cited by 77 · see citing works
“Additional associations of several genetic variations further downstream in the GABRA2 gene with cocaine addiction were also found, as reported in studies of alcohol dependence (17, 18).”
Result
Genetics of alcohol dependence
Kimura, M., & Higuchi, S. (2011) · Psychiatry and Clinical Neurosciences · doi:10.1111/j.1440-1819.2011.02190.x · Cited by 77 · see citing works
Co-occurring risk factors for alcohol dependence and habitual smoking: update on findings from the Collaborative Study on the Genetics of Alcoholism.
Grucza, R. A., & Bierut, L. J. (2006) · PubMed Central · Cited by 77 · see citing works
Genetic influences on conduct disorder
Salvatore, J. E., & Dick, D. M. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.034 · Cited by 76 · see citing works
Gene–environment interactions and alcohol use and dependence: current status and future challenges
van der Zwaluw, C. S., & Engels, R. C. M. E. (2009) · Addiction · doi:10.1111/j.1360-0443.2009.02563.x · Cited by 73 · see citing works
“While most studies focused upon dopamine transporter and receptor genes [10–12], others examined the roles of gamma aminobutyric acid (GABA) receptor genes [13–15], serotonin transporter and receptor genes [15–17] and opioid receptor genes [18,19].”
Background
Advances in Electrophysiological Research
Kamarajan, C. (2015) · Alcohol Research: Current Reviews · doi:10.35946/arcr.v37.1.05 · Cited by 72 · see citing works
“2004) and replicated by many other studies worldwide (Covault et al. 2004; Fehr et al. 2006; Lappalainen et al. 2005; Philibert et al. 2009; Soyka et al. 2008).”
Result
Effects of Opioid Receptor Gene Variation on Targeted Nalmefene Treatment in Heavy Drinkers
Arias, A. J., Armeli, S., Gelernter, J. E., Covault, J., Kallio, A., Karhuvaara, S., Koivisto, T., Mäkelä, R., & Kranzler, H. R. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00735.x · Cited by 70 · see citing works
“variation in GABRA2, which encodes the alpha-2 subunit of the GABA-A receptor, is associated with alcohol dependence (Covault et al., 2004; Edenberg et al., 2004; Enoch et al., 2006; Fehr et al., 2006; Lappalainen et al., 2005; Soyka et al., 2007).”
Background
Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq
Hawkins, N. A., Zachwieja, N. J., Miller, A. R., Anderson, L. L., & Kearney, J. A. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006398 · Cited by 71 · see citing works
Early cannabis use and DSM‐IV nicotine dependence: a twin study
Arpana Agrawal, A., Lynskey, M. T., Pergadia, M. L., Bucholz, K. K., Heath, A. C., Martin, N. G., & Madden, P. A. F. (2008) · Addiction · doi:10.1111/j.1360-0443.2008.02354.x · Cited by 69 · see citing works
“Initially identified for its role in alcohol dependence [49–52], recent work has implicated polymorphisms in the GABRA2 gene for their role in cannabis dependence [53], ND [54] and conduct disorder [55].”
Background
Role of GABRA2 in Moderating Subjective Responses to Alcohol
Roh, S., Matsushita, S., Hara, S., Maesato, H., Matsui, T., Suzuki, G., Miyakawa, T., Ramchandani, V. A., Li, T., & Higuchi, S. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01357.x · Cited by 68 · see citing works
“Previous association studies have shown the SNP4 A-allele, SNP5 G-allele, and SNP6 C-allele to be over-represented among subjects with alcohol dependence (Covault et al., 2004; Lappalainen et al., 2005).”
BackgroundMethodResultInfluential
Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: A review of human brain oscillations as effective endophenotypes
Rangaswamy, M., & Bernice Porjesz, A. (2008) · Brain Research · doi:10.1016/j.brainres.2008.06.053 · Cited by 66 · see citing works
“…acid (GABA) A receptor, alph aminobutyric acid (GABA) A receptor, beta 1; metabotropic 8; GWAS, Genome-wide Associ mGluR, metabotropic glutamate receptors; Pedigree Disequilibrium Test; SNP, Single-nu 0006-8993/$ – see front matter © 2008 Elsevi doi:10.1016/j.brainres.2008.06.053 A B S T R A C T”
BackgroundInfluential
GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential
Dharavath, R. N., Pina‐Leblanc, C., Tang, V. M., Sloan, M. E., Nikolova, Y. S., Pangarov, P., Ruocco, A. C., Shield, K. D., Voineskos, D., Blumberger, D. M., et al. (2023) · Frontiers in Neural Circuits · doi:10.3389/fncir.2023.1218737 · Cited by 63 · see citing works
GENETIC STUDY: H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse‐associated risk for alcohol consumption and dependence
Nelson, E. C., Arpana Agrawal, A., Pergadia, M. L., Wang, J. C. C., Whitfield, J. B., Saccone, F. S., Kern, J., Grant, J. D., Schrage, A. J., Rice, J. P., et al. (2009) · Addiction Biology · doi:10.1111/j.1369-1600.2009.00181.x · Cited by 63 · see citing works
“2009)] and effects [GABRA2 (Covault et al. 2004; Edenberg et al. 2004; Lappalainen et al. 2005; Fehr et al. 2006), CHRM2 (Wang et al.”
Pharmacogenetics of Alcohol and Alcohol Dependence Treatment
Kranzler, H. R., & Edenberg, H. J. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210791516387 · Cited by 62 · see citing works
“Subsequent case-control studies replicated this finding, providing evidence of association to alcohol dependence [67-71].”
BackgroundResult
A Polymorphism in GABRA2 Is Associated With the Medial Frontal Response to Alcohol Cues in an fMRI Study
Kareken, D. A., Liang, T., Wetherill, L. F., Džemidžić, M., Bragulat, V., Cox, C., Talavage, T. M., O’Connor, S., & Foroud, T. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01293.x · Cited by 62 · see citing works
“Results with SNPs in high LD with rs279871 (r2 > 0.70) suggest that there may be an allelic dosage effect, with those individuals homozygous for the high risk allele having the greatest risk for alcohol dependence (Covault et al., 2004; Fehr et al., 2006).”
BackgroundResultInfluential
Heritability and molecular‐genetic basis of resting EEG activity: A genome‐wide association study
Malone, S. M., Burwell, S. J., Vaidyanathan, U., Miller, M. B., McGue, M. K., & Iacono, W. G. (2014) · Psychophysiology · doi:10.1111/psyp.12344 · Cited by 61 · see citing works
A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity
Schuckit, M. A. (2018) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13628 · Cited by 59 · see citing works
“…oral and IV alcohol challenges indicate relationships to sensitivity and heavier drinking for G-alleles of rs279858 (e.g., Arias et al., 2013; Covault et al., 2004, 2008; Kosobud et al., 2015; Lappalainen et al., 2005; Pierucci-Lagha et al., 2005; Roh et al., 2011; Uhart et al., 2012);…”
Background
Identification of a Functional Non-coding Variant in the GABAA Receptor α2 Subunit of the C57BL/6J Mouse Reference Genome: Major Implications for Neuroscience Research
Mulligan, M. K., Abreo, T. J., Neuner, S. M., Parks, C., Watkins, C. E., Houseal, M. T., Shapaker, T. M., Hook, M., Tan, H., Wang, X., et al. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00188 · Cited by 56 · see citing works
“Genetic variation at this locus has been linked to alcohol dependence (Covault et al., 2004; Edenberg et al., 2004; Lappalainen et al., 2005; Agrawal et al., 2006; Enoch et al., 2006; Fehr et al., 2006; Lind et al., 2008a; Lind et al., 2008b; Soyka et al., 2008; Villafuerte et al., 2013; Li et al.,…”
Background
Human γ‐aminobutyric acid A receptor α2 gene moderates the acute effects of alcohol and brain mRNA expression
Haughey, H. M., Ray, L. A., Finan, P. H., Villanueva, R. E., Niculescu, M., & Hutchison, K. E. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00369.x · Cited by 58 · see citing works
“These findings were replicated and extended by Covault et al. (2004) and others (Dick & Bierut 2006; Drgon et al. 2006; Enoch et al. 2006; Fehr et al. 2006; Lappalainen et al. 2005).”
BackgroundResult
Endophenotypes for Alcohol Use Disorder: An Update on the Field
Salvatore, J. E., Gottesman, I. I., & Dick, D. M. (2015) · Current Addiction Reports · doi:10.1007/s40429-015-0046-y · Cited by 58 · see citing works
Intergenerational influences on early alcohol use: Independence from the problem behavior pathway
Kerr, D., Capaldi, D. M., Pears, K. C., & Owen, L. D. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000430 · Cited by 57 · see citing works
Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study
Agrawal, A., Pergadia, M. L., Saccone, S. F., Hinrichs, A. L., Lessov‐Schlaggar, C. N., Saccone, N. L., Neuman, R. J., Breslau, N., Johnson, E., Hatsukami, D., et al. (2008) · Addiction · doi:10.1111/j.1360-0443.2008.02236.x · Cited by 56 · see citing works
“This finding was replicated subsequently across independent US [36], Russian [37] and German [38] data sets.”
Result
Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition
Anstee, Q. M., Knapp, S., Maguire, E. P., Hosie, A. M., Thomas, P., Mortensen, M., Bhome, R., Martínez, A., Walker, S. E., Dixon, C. I., et al. (2013) · Nature Communications · doi:10.1038/ncomms3816 · Cited by 56 · see citing works
The Role of GABRA2 in Alcohol Dependence, Smoking, and Illicit Drug Use in an Australian Population Sample
Lind, P. A., Macgregor, S., Agrawal, A., Montgomery, G. W., Heath, A. C., Martin, N. G., & Whitfield, J. B. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00768.x · Cited by 55 · see citing works
“(2005) where individuals carrying G alleles were less sensitive to the effect of alcohol and hence more likely to become alcohol dependent and in 3 studies where the G allele was significantly over-represented among alcoholics (Covault et al., 2004; Fehr et al., 2006; Lappalainen et al., 2005).”
BackgroundMethodResultInfluential
Gene-Environment Interplay in Adolescent Drinking Behavior
Rose, R. J., & Dick, D. M. (2004) · Europe PMC (PubMed Central) · Cited by 54 · see citing works
Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk
Heitzeg, M. M., Villafuerte, S. M., Weiland, B. J., Enoch, M., Burmeister, M., Zubieta, J., & Zucker, R. A. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.161 · Cited by 54 · see citing works
REVIEW: A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse models
Ehlers, C. L., Walter, N. A. R., Dick, D. M., Buck, K. J., & Crabbe, J. C. (2010) · Addiction Biology · doi:10.1111/j.1369-1600.2009.00195.x · Cited by 53 · see citing works
“(Covault et al. 2004, 2008; Edenberg et al. 2004; Lappalainen et al. 2005; Dick et al. 2006c; Fehr et al. 2006; Matthews et al. 2007).”
Background
Genetic influences on alcohol use across stages of development:GABRA2and longitudinal trajectories of drunkenness from adolescence to young adulthood
Dick, D. M., Cho, S. B., Latendresse, S. J., Alıev, F., Nürnberger, J. I., Edenberg, H. J., Schuckit, M. A., HESSELBROCK, V. M., Bernice Porjesz, A., Bucholz, K. K., et al. (2013) · Addiction Biology · doi:10.1111/adb.12066 · Cited by 52 · see citing works
“2 results for rs279858 since it has been one of the most widely studied and replicated SNPs in GABRA2 (Covault et al. 2004; Edenberg et al. 2004; Lappalainen et al. 2005; Lind et al. 2008; Bierut et al. 2010).”
Using genetic information from candidate gene and genome‐wide association studies in risk prediction for alcohol dependence
Yan, J., Alıev, F., Webb, B. T., Kendler, K. S., Williamson, V. S., Edenberg, H. J., Arpana Agrawal, A., Kos, M. Z., Almasy, L. A., Nürnberger, J. I., et al. (2013) · Addiction Biology · doi:10.1111/adb.12035 · Cited by 52 · see citing works
“Controls reported consuming alcohol but did not have a diagnosis of AD or alcohol abuse by any of the diagnostic criteria assessed by SSAGA and did not meet diagnostic criteria for dependence on cocaine, marijuana, opioids, sedatives or stimulants.”

Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis
Fehr, C., Sander, T., Tadić, A., Lenzen, K. P., Anghelescu, I. G., Klawe, C., Dahmen, N., Schmidt, L. G., & Szegedi, A. (2006) · Psychiatric Genetics · doi:10.1097/01.ypg.0000185027.89816.d9 · Cited by 179 · see citing works
GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence
Soyka, M., Preuss, U. W., HESSELBROCK, V. M., Zill, P., Koller, G., & Bondy, B. (2007) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.11.006 · Cited by 162 · see citing works
GABRG1andGABRA2Variation Associated with Alcohol Dependence in African Americans
Ittiwut, C., Yang, B., Kranzler, H. R., Anton, R. F., Hirunsatit, R., Weiss, R. D., Covault, J., Farrer, L. A., & Gelernter, J. E. (2011) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2011.01637.x · Cited by 42 · see citing works
Association of GABAA receptor α2 subunit gene (GABRA2) with alcohol dependence-related aggressive behavior
Štrac, D. Š., Erjavec, G. N., Perković, M. N., Šviglin, K. N., Borovečki, F., & Pivac, N. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.06.010 · Cited by 16 · see citing works
The lack of association of GABRA2 polymorphism and alcohol dependence in Croatian population
Štrac, D. Š., Gordana, N. C., Nikolac, M., Nenadić-Šviglin, K., Mustapić, M., Muck-Šeler, D., & Pivac, N. (2011) · Institutional Repository of the Ruđer Bošković Institute (Ruđer Bošković Institute)

Authors: Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., & Kranzler, H. R.
Affiliations: University of Connecticut (US)
Yale University (US)
Corresponding author: Kranzler, Henry R.
ORCID: Covault, Jonathan
Gelernter, Joel
Hesselbrock, Victor
Kranzler, Henry R.
Venue: American Journal of Medical Genetics Part B Neuropsychiatric Genetics
Publisher: Wiley
Published: 2004-07-06
Volume: 129B
Issue: 1
Pages: 104-109
ISSN: 1552-4841 (ISSN-L)
1552-485X
DOI: 10.1002/ajmg.b.30091
OpenAlex: W1990779093
Cited by: 273
References: 30
Citations by year: 2026: 2 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 12 · 2017: 9 · 2016: 14 · 2015: 20 · 2014: 18 · 2013: 12 · 2012: 26
FWCI: 9.79
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p50aa003510-27)
National Institute on Alcohol Abuse and Alcoholism (K24 AA13736, R01 AA 11330, R01AA011330, K24AA013736, P50- AA03510)
National Institute on Drug Abuse (K24 DA15105, K24DA015105)
National Center for Research Resources (M01RR006192, M01 RR 06192)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: alcoholism, GABRA2, haplotype association, single nucleotide polymorphisms, genetic susceptibility, chromosome 4p, European Americans
MeSH terms: Adult, Alcoholism, Alleles, Chromosomes, Human, Pair 4, DNA, DNA Mutational Analysis, Female, Gene Frequency, Multigene Family, Genotype, Haplotypes, Humans, Male, Middle Aged, Receptors, GABA-A, Polymorphism, Single Nucleotide, Protein Subunits

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Allelic and haplotypic association of GABRA2 with alcohol dependence

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