Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study.

paper Cited Public

Authors: Melroy, Whitney E; Stephens, Sarah H; Sakai, Joseph T; Kamens, Helen M; McQueen, Matthew B; Corley, Robin P; Stallings, Michael C; Hopfer, Christian J; Krauter, Kenneth S; Brown, Sandra A; Hewitt, John K; Ehringer, Marissa A
Year: 2014
Journal: Behavior genetics
PMID: 24687270
DOI: 10.1007/s10519-014-9653-y
PMCID: PMC4098655

#	Section	Preview
20	Materials and Methods — Statistical Analysis — Analysis of the GADD sample — Conduct disorder	For lifetime CD symptoms, data were drawn from wave 1. All of the subjects were assessed using DSM…
21	Materials and Methods — Statistical Analysis — Analysis of the GADD sample — Adolescent/young adult alcohol abuse and dependence	Adolescent/young adult AAD symptoms were drawn from wave 1 of data collection. All items were…
22	Materials and Methods — Statistical Analysis — Analysis of the GADD sample — Adult alcohol abuse and dependence	Adult AAD symptoms were drawn from wave 2. All items were assessed using DSM IV criteria. Only…
23	Materials and Methods — Statistical Analysis — Combined Analysis of the CADD and GADD samples	To increase statistical power, the GADD and CADD samples were combined after the data were cleaned…
24	Materials and Methods — Statistical Analysis — Statistical Analysis	The data were analyzed using an additive genetic model in a family-based association test performed…
25	Materials and Methods — Statistical Analysis — Correction for multiple testing	We used the spectral decomposition (SNPSpD) method (Nyholt 2004) to estimate the minimum p-value…
26	Results	The phenotypic characteristics between the CADD clinical and GADD samples are comparable (Figure 1).…
27	Results	The minor alleles were identical in EAs and Hispanics and the minor allele frequencies were similar…
28	Results	In EA and Hispanic subjects in the CADD, the SNPs were somewhat correlated with an r2 > 0.50, with…
29	Results	As expected from previous analyses of these SNPs, no significant associations were detected with AAD…
30	Results	Rs9291283 was suggestively associated with AAD in adulthood in the CADD sample (Table II). Results…
31	Results	In the GADD sample, rs9291283 was associated with CD (Table III). Results from spectral…
32	Results	In the combined CADD and GADD analysis, rs9291283 was nominally associated with AAD in adulthood (p…
33	Discussion	The goals of this study were to expand on previous work demonstrating strong associations of GABRA2…
34	Discussion	In considering the SNPs in high LD and comparing results to previous reports, our findings are in…
35	Discussion	(2006) and Sakai (2010) studies, rs279871 was found to be associated with adolescent CD, yet here…
36	Discussion	establishing CD symptoms while our study used primarily DSM IV criteria. Although the DSM IV and DSM…
37	Discussion	Rs9291283 was nominally associated with adult AAD in the CADD and combined CADD and GADD samples.…
38	Discussion	et al. 2009; Bierut et al. 2010; Olfson and Bierut 2012; Philibert et al. 2009; Ittiwut et al. 2012;…
39	Discussion	interest is the study by Onori et al. (2010) examining alcohol use disorders; no significant…

Citation	PMID	DOI	Status
Anchordoquy, HC et al., Behavior genetics, 2003, Genotyping of three candidate genes after whole-genome preamplification of DNA collected from buccal cells.	12645824	10.1023/a:1021007701808	Cited
Barrett, JC et al., Bioinformatics, 2005, Haploview: analysis and visualization of LD and haplotype maps.	15297300	10.1093/bioinformatics/bth457	Cited
Bierut, LJ et al., Proc Natl Acad Sci U S A, 2010, A genome-wide association study of alcohol dependence.	20202923	10.1073/pnas.0911109107	Primary
Button, TM et al., Drug and alcohol dependence, 2007, The role of conduct disorder in explaining the comorbidity between alcohol and illicit drug dependence in adolescence.	16956733	10.1016/j.drugalcdep.2006.07.012	Cited
Button, TM et al., Twin Res Hum Genet, 2006, Examination of the causes of covariation between conduct disorder symptoms and vulnerability to drug dependence.	16611466	10.1375/183242706776402993	Cited
Cottler, LB et al., Recent Dev Alcohol, 1990, Operationalization of alcohol and drug dependence criteria by means of a structured interview.	2333396	—	Cited
Covault, J et al., Am J Med Genet B Neuropsychiatr Genet, 2004, Allelic and haplotypic association of GABRA2 with alcohol dependence.	15274050	10.1002/ajmg.b.30091	Cited
Covault, J et al., Neuropsychopharmacology, 2008, Markers in the 5′-region of GABRG1 associate to alcohol dependence and are in linkage disequilibrium with markers in the adjacent GABRA2 gene.	17507911	10.1038/sj.npp.1301456	Cited
Devaud, LL et al., Journal of neurochemistry, 1997, Bidirectional alterations of GABA(A) receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal.	9202302	10.1046/j.1471-4159.1997.69010126.x	Cited
Devaud, LL et al., The Journal of pharmacology and experimental therapeutics, 1996, Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal.	8768698	—	Cited
Dick, DM et al., Behav Genet, 2006, The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages.	16557364	10.1007/s10519-005-9041-8	Primary
Dick, DM et al., Twin Res Hum Genet, 2013, How phenotype and developmental stage affect the genes we find: GABRA2 and impulsivity.	23561058	10.1017/thg.2013.20	Primary
Dixon, CI et al., Proceedings of the National Academy of Sciences of the United States of America, 2010, Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors.	20133874	10.1073/pnas.0910117107	Cited
Dodd, PR et al., Journal of neurochemistry, 1992, Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver.	1328522	10.1111/j.1471-4159.1992.tb08467.x	Cited
Drgon, T et al., Am J Med Genet B Neuropsychiatr Genet, 2006, Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions.	16894595	10.1002/ajmg.b.30349	Cited
Edenberg, HJ et al., Am J Hum Genet, 2004, Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.	15024690	10.1086/383283	Primary
Engin, E et al., Pharmacology & therapeutics, 2012, alpha2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders.	22921455	10.1016/j.pharmthera.2012.08.006	Cited
Enoch, MA et al., Neuropsychopharmacology, 2009, GABRG1 and GABRA2 as independent predictors for alcoholism in two populations.	18818659	10.1038/npp.2008.171	Cited
Enoch, MA, Curr Psychiatry Rep, 2013, Genetic influences on the development of alcoholism.	24091936	10.1007/s11920-013-0412-1	Cited
Fehr, C et al., Psychiatr Genet, 2006, Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis.	16395124	10.1097/01.ypg.0000185027.89816.d9	Cited
Gelhorn, H et al., J Am Acad Child Adolesc Psychiatry, 2008, Toward DSM-V: an item response theory analysis of the diagnostic process for DSM-IV alcohol abuse and dependence in adolescents.	18827724	10.1097/CHI.0b013e318184ff2e	Cited
Gelhorn, HL et al., J Child Psychol Psychiatry, 2005, Genetic and environmental influences on conduct disorder: symptom, domain and full-scale analyses.	15877764	10.1111/j.1469-7610.2004.00373.x	Cited
Grobin, AC et al., Psychopharmacology (Berl), 1998, The role of GABA(A) receptors in the acute and chronic effects of ethanol.	9768538	10.1007/s002130050685	Cited
Heath, AC et al., Psychol Med, 1997, Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men.	9403910	10.1017/s0033291797005643	Cited
Herman, JP et al., Annals of the New York Academy of Sciences, 2004, Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration.	15240350	10.1196/annals.1296.004	Cited
Hewitt, JK, Behavior genetics, 2012, Editorial policy on candidate gene association and candidate gene-by-environment interaction studies of complex traits.	21928046	10.1007/s10519-011-9504-z	Cited
Hicks, BM et al., Behavior genetics, 2011, Psychometric and genetic architecture of substance use disorder and behavioral disinhibition measures for gene association studies.	21153693	10.1007/s10519-010-9417-2	Cited
Ittiwut, C et al., Alcoholism, clinical and experimental research, 2012, GABRG1 and GABRA2 variation associated with alcohol dependence in African Americans.	21919924	10.1111/j.1530-0277.2011.01637.x	Cited
Johnson, SW et al., The Journal of neuroscience : the official journal of the Society for Neuroscience, 1992, Opioids excite dopamine neurons by hyperpolarization of local interneurons.	1346804	10.1523/JNEUROSCI.12-02-00483.1992	Cited
Kamens, HM et al., Genes Brain Behav, 2013, Nominal association with CHRNA4 variants and nicotine dependence.	23350800	10.1111/gbb.12021	Cited
Kendler, KS et al., Arch Gen Psychiatry, 2003, The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women.	12963675	10.1001/archpsyc.60.9.929	Cited
Kuperman, S et al., Am J Psychiatry, 2001, Developmental sequence from disruptive behavior diagnosis to adolescent alcohol dependence.	11729019	10.1176/appi.ajp.158.12.2022	Primary
Langenbucher, JW et al., J Abnorm Psychol, 2004, An application of item response theory analysis to alcohol, cannabis, and cocaine criteria in DSMIV.	14992659	10.1037/0021-843X.113.1.72	Cited
Lappalainen, J et al., Alcohol Clin Exp Res, 2005, Association between alcoholism and gamma-amino butyric acid alpha2 receptor subtype in a Russian population.	15834213	10.1097/01.alc.0000158938.97464.90	Cited
Lewohl, JM et al., Brain Res, 1997, Expression of the alpha 1, alpha 2 and alpha 3 isoforms of the GABAA receptor in human alcoholic brain.	9098573	10.1016/s0006-8993(96)01396-0	Cited
Li, D et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2013, Association of Gamma-Aminobutyric Acid A Receptor alpha2 Gene (GABRA2) with Alcohol Use Disorder.	24136292	10.1038/npp.2013.291	Cited
Lind, PA et al., Alcohol Clin Exp Res, 2008, The role of GABRA2 in alcohol dependence, smoking, and illicit drug use in an Australian population sample.	18727688	10.1111/j.1530-0277.2008.00768.x	Cited
Lydall, GJ et al., Neurosci Lett, 2011, Genetic association study of GABRA2 single nucleotide polymorphisms and electroencephalography in alcohol dependence.	21683760	10.1016/j.neulet.2011.05.240	Cited
Martijena, ID et al., Synapse, 2002, Gabaergic modulation of the stress response in frontal cortex and amygdala.	12112401	10.1002/syn.10085	Cited
Martin, CS et al., J Abnorm Psychol, 2006, Item response theory analysis of diagnostic criteria for alcohol and cannabis use disorders in adolescents: implications for DSM-V.	17100538	10.1037/0021-843X.115.4.807	Cited
Matthews, AG et al., J Stud Alcohol Drugs, 2007, The role of the GABRA2 polymorphism in multiplex alcohol dependence families with minimal comorbidity: within-family association and linkage analyses.	17690794	10.15288/jsad.2007.68.625	Cited
Matthews, DB et al., Journal of neurochemistry, 1998, Differential regulation of GABA(A) receptor gene expression by ethanol in the rat hippocampus versus cerebral cortex.	9489737	10.1046/j.1471-4159.1998.70031160.x	Cited
Mitsuyama, H et al., Alcoholism, clinical and experimental research, 1998, GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and protein expression in the frontal cortex of human alcoholics.	9660306	—	Cited
Moss, HB et al., Drug and alcohol dependence, 2001, Comorbid disruptive behavior disorder symptoms and their relationship to adolescent alcohol use disorders.	11470343	10.1016/s0376-8716(00)00233-7	Cited
Nyholt, DR, American journal of human genetics, 2004, A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other.	14997420	10.1086/383251	Cited
Olfson, E et al., Alcoholism, clinical and experimental research, 2012, Convergence of Genome-Wide Association and Candidate Gene Studies for Alcoholism.	22978509	10.1111/j.1530-0277.2012.01843.x	Primary
Onori, N et al., Alcohol Clin Exp Res, 2010, GABRA2 and alcohol use disorders: no evidence of an association in an Italian case-control study.	20102561	10.1111/j.1530-0277.2009.01135.x	Cited
Palmer, RH et al., Addict Behav, 2013, Prospective effects of adolescent indicators of behavioral disinhibition on DSM-IV alcohol, tobacco, and illicit drug dependence in young adulthood.	23685327	10.1016/j.addbeh.2013.03.021	Cited
Petrill, SAPR et al., Oxford University Press, 2003, Nature, nurture, and the transition to early adolescence.	—	—	—
Philibert, RA et al., Psychiatric genetics, 2009, Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.	19672139	10.1097/YPG.0b013e3283208026	Cited
Rabinowitz, D et al., Hum Hered, 2000, A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information.	10782012	10.1159/000022918	Cited
Rhea, SA et al., Twin Res Hum Genet, 2006, Colorado Twin Registry.	17254434	10.1375/183242706779462895	Cited
Robins, LN et al., Arch Gen Psychiatry, 1981, National Institute of Mental Health Diagnostic Interview Schedule. Its history, characteristics, and validity.	6260053	10.1001/archpsyc.1981.01780290015001	Cited
Rose, RJ et al., Alcoholism, clinical and experimental research, 2004, Genetic and environmental effects on conduct disorder and alcohol dependence symptoms and their covariation at age 14.	15597087	10.1097/01.alc.0000141822.36776.55	Cited
Saha, TD et al., Psychol Med, 2006, Toward an alcohol use disorder continuum using item response theory: results from the National Epidemiologic Survey on Alcohol and Related Conditions.	16563205	10.1017/S003329170600746X	Cited
Sakai, JT et al., Drug Alcohol Depend, 2010, Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems, controls and available first degree relatives.	19783384	10.1016/j.drugalcdep.2009.08.015	Cited
Shaffer, D et al., J Am Acad Child Adolesc Psychiatry, 1993, The Diagnostic Interview Schedule for Children-Revised Version (DISC-R): I. Preparation, field testing, interrater reliability, and acceptability.	8496128	10.1097/00004583-199305000-00023	Cited
Slutske, WS et al., J Abnorm Psychol, 1997, Modeling genetic and environmental influences in the etiology of conduct disorder: a study of 2,682 adult twin pairs.	9131847	10.1037//0021-843x.106.2.266	Cited
Slutske, WS et al., J Abnorm Psychol, 1998, Common genetic risk factors for conduct disorder and alcohol dependence.	9715572	10.1037//0021-843x.107.3.363	Cited
Soyka, M et al., J Psychiatr Res, 2008, GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence.	17207817	10.1016/j.jpsychires.2006.11.006	Cited
Spielman, RS et al., American journal of human genetics, 1993, Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).	8447318	—	Cited
Stallings, MC et al., Arch Gen Psychiatry, 2005, A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence.	16143736	10.1001/archpsyc.62.9.1042	Cited
Stallings, MC et al., Drug and alcohol dependence, 2003, A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence.	12757967	10.1016/s0376-8716(03)00031-0	Cited
Steffensen, SC et al., The Journal of neuroscience : the official journal of the Society for Neuroscience, 1998, Electrophysiological characterization of GABAergic neurons in the ventral tegmental area.	9742167	10.1523/JNEUROSCI.18-19-08003.1998	Cited
Stevens, G et al., Bull World Health Organ, 2009, Global health risks: progress and challenges.	19784438	10.2471/BLT.09.070565	Cited
Villafuerte, S et al., Molecular psychiatry, 2011, Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism.	21483437	10.1038/mp.2011.33	Cited
Vrieze, SI et al., Am J Psychiatry, 2012, Decline in genetic influence on the cooccurrence of alcohol, marijuana, and nicotine dependence symptoms from age 14 to 29.	22983309	10.1176/appi.ajp.2012.11081268	Cited
White, HR et al., Psychol Addict Behav, 2001, Psychopathology as a predictor of adolescent drug use trajectories.	11563798	—	Cited

In this knowledge base

Title	Year	PMID
Genetic influences on conduct disorder.	2018	27350097
Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps.	2018	29227573
A GABRA2 polymorphism improves a model for prediction of drinking initiation.	2017	28847377
Mechanisms in the relation between GABRA2 and adolescent externalizing problems.	2016	25804982

External

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GABA<sub>A</sub> Receptor Subtype Mechanisms and the Abuse-Related Effects of Ethanol: Genetic and Pharmacological Evidence.	Chandler CM et al.	—	2018	→
Genetic influences on conduct disorder.	Salvatore JE et al.	—	2018	→
Impulsivity Dimensions and Risky Sex Behaviors in an At-Risk Young Adult Sample.	Curry I et al.	—	2018	→
Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps.	Dick DM et al.	—	2018	→
A GABRA2 polymorphism improves a model for prediction of drinking initiation.	Kuperman S et al.	—	2017	→
GABA<sub>A</sub> receptor subtype involvement in addictive behaviour.	Stephens DN et al.	—	2017	→
Unique and interactive effects of impulsivity facets on reckless driving and driving under the influence in a high-risk young adult sample.	Luk JW et al.	—	2017	→
Mechanisms in the relation between GABRA2 and adolescent externalizing problems.	Wang FL et al.	—	2016	→
Risky driving and sexual behaviors as developmental outcomes of co-occurring substance use and antisocial behavior.	Luk JW et al.	—	2016	→
Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs.	Vicente-Rodríguez M et al.	—	2014	→