Mechanisms in the relation between GABRA2 and adolescent externalizing problems.

paper Cited Public

Authors: Wang, Frances L; Chassin, Laurie; Geiser, Christian; Lemery-Chalfant, Kathryn
Year: 2016
Journal: European child & adolescent psychiatry
PMID: 25804982
DOI: 10.1007/s00787-015-0703-7
PMCID: PMC4583314

#	Section	Preview
0	Introduction	Conduct problems, alcohol problems, and hyperactive–inattentive symptoms display moderate-to-high…
1	Introduction	Along these lines, previous studies have shown associations between GABRA2 variation and adolescent…
2	Introduction	Interestingly, although Trucco et al. [12] did not find a direct effect of GABRA2 on adolescent…
3	Introduction	If GABRA2 does confer risk for a broad spectrum of externalizing behaviors, it would be important to…
4	Introduction	Taken together, previous research suggests that GABRA2 relates to some facets of disinhibition and…
5	Introduction	Understanding whether GABRA2 predicts these externalizing problems indirectly, through…
6	Introduction	Two particularly important facets of disinhibition in adolescence are sensation seeking and…
7	Introduction	Research demonstrates that impulsivity and sensation seeking relate differentially to adolescent…
8	Introduction	Researchers posited that perhaps impulsivity more broadly predicts all three externalizing problems…
9	Introduction	Of note, the literature on GABRA2 has largely focused on single nucleotide polymorphisms (SNPs)…
10	Introduction	block and externalizing disorders [17, 19, 21]. Interestingly, one study showed that alcoholics with…
11	Introduction	Based on this literature, the major aim of the current study was to examine associations between…
12	Introduction	models were tested for several reasons. First, because stability in problem behaviors might be more…
13	Introduction	We hypothesized that GABRA2 would predict sensation seeking, but not impulsivity, based on results…
14	Introduction	In testing these questions, it is important to acknowledge that a limitation of the candidate gene…
15	Methods — Participants	Participants were drawn from the third generation of a longitudinal study of familial alcoholism…
16	Methods — Participants	(e.g., problems with recall, social desirability), we excluded those cases, resulting in a final…
17	Methods — Recruitment and procedure	In the larger study, families with at least one alcoholic parent (from the first-generation) were…
18	Methods — Measures — Demographics	Adolescents self-reported their gender, age, and ethnicity. See Table 1.
19	Methods — Measures — Genotyping and SNP selection	Extraction of DNA, standardization and plating were completed in the Department of Psychiatry at the…

Name	Type
AA/AG genotype local	variant
A allele	cohort
addiction	phenotype
adolescent alcohol phenotypes local	phenotype
adolescent alcohol use	phenotype
adolescent conduct disorder local	phenotype
adolescent conduct problems	phenotype
adolescent externalizing symptoms local	phenotype
Adolescent hyperactive–inattentive symptoms local	phenotype
adolescent impulsivity local	phenotype
adolescent rule-breaking behaviors local	phenotype
adolescents	cohort
adolescent sample	cohort
adolescent sensation seeking local	phenotype
adolescents’ sensation seeking local	phenotype
adolescent substance use	phenotype
adult alcohol phenotypes local	phenotype
adult alcohol use disorders local	phenotype
adult antisocial behavior	phenotype
adult drug phenotypes local	phenotype
adult sample	cohort
adults’ lifetime alcohol problems local	phenotype
adult substance use disorders local	phenotype
adult substance use phenotypes local	phenotype
age	phenotype
alcohol	phenotype
Alcohol Dependence Symptoms	phenotype
alcoholism	phenotype
Alcohol Problems	phenotype
Alcohol Use Disorder	phenotype
AMR 1000 Genomes Phase 1 population local	cohort
ancestry	phenotype
attention deficit hyperactivity disorder	phenotype
barbiturates	drug
Baseline externalizing problems local	phenotype
behavioral disinhibition	phenotype
benzodiazepines	drug
Caucasian sample	cohort
Cognitive Control System local	anatomy
conduct disorder	phenotype
disinhibition	phenotype
dopamine	drug
drug	drug
drug dependence	phenotype
ethanol consumption	phenotype
EUR 1000 Genomes Phase 1 population local	cohort
externalizing disorders	phenotype
externalizing outcomes	phenotype
externalizing-related problems local	phenotype
families without parental alcoholism local	cohort
families with parental alcoholism local	cohort
Family History Density composite local	phenotype
Family history of drinking local	phenotype
fathers	cohort
FHD	cohort
first-generation local	cohort
GABA	phenotype
GABRA2	gene
GABRA2 AA/AG genotype local	variant
GABRA2 major haplotype local	variant
GABRA2 minor haplotype local	variant
GABRA2 polymorphism local	variant
G allele	variant
GG genotype local	variant
Grandparents local	cohort
higher impulsivity local	phenotype
higher sensation seeking local	phenotype
high-risk sample	cohort
Hispanic	phenotype
hyperactive–inattentive symptoms local	phenotype
Hyperactive-inattentive symptoms local	phenotype
Hyperactive–inattentive symptoms local	phenotype
impulsivity	phenotype
intermediate phenotypes	phenotype
Lifetime alcohol consequences local	phenotype
lifetime alcohol use	phenotype
low trait anxiety local	phenotype
mid-adolescent rule-breaking behaviors local	phenotype
mothers	cohort
negative affect	phenotype
NEO impulsiveness local	phenotype
NEO-Impulsiveness local	phenotype
NEO impulsivity local	phenotype
non-Hispanic Caucasian local	cohort
Non-Hispanic Caucasian local	phenotype
non-Hispanic Caucasian ancestry local	cohort
non-Hispanic Caucasian ancestry local	phenotype
Non-Hispanic Caucasian ancestry local	phenotype
non-Hispanic Caucasian population local	cohort
Non-Hispanic Caucasians local	cohort
novelty seeking	phenotype
parents	cohort
participants	cohort
personality/temperament local	phenotype
personality traits	phenotype
positive subjective alcohol effects local	phenotype
positive subjective response local	phenotype
problem behavior	phenotype
race/ethnicity	phenotype
Recanting local	phenotype
reward system	anatomy
rs279858	variant
rule-breaking behaviors local	phenotype
second-generation local	cohort
self-reported ethnicity local	phenotype
sex	phenotype
SNP	cohort
Study cohort (N=292) local	cohort
substance use	phenotype
symptoms	phenotype
T1 alcohol problems local	phenotype
T1 conduct problems local	phenotype
T1 hyperactive–inattentive symptoms local	phenotype
T1 symptoms local	phenotype
T2 alcohol problems local	phenotype
T2 conduct problems local	phenotype
T2 hyperactive–inattentive symptoms local	phenotype
third-generation local	cohort
Third Generation Longitudinal Study of Familial Alcoholism local	cohort
trait anxiety	phenotype
ventral tegmental area	anatomy

Citation	PMID	DOI	Status
Achenbach, TM et al., Manual for the ASEBA School-Age Forms & Profiles, 2001	—	—	—
Agrawal, A et al., Behav Genet, 2006, Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample.	16622805	10.1007/s10519-006-9069-4	Primary
Barnard, EA et al., Pharmacol Rev, 1998, Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.	9647870	—	Cited
Bates, ME et al., Psychol Addict Behav, 1995, Personality environment constellations and alcohol use: a process-oriented study of intraindividual change during adolescence.	—	—	—
Bauer, LO et al., Alcohol Clin Exp Res, 2007, Variation in GABRA2 predicts drinking behavior in project MATCH subjects.	17949392	10.1111/j.1530-0277.2007.00517.x	Cited
Castellanos-Ryan, N et al., Alcohol Clin Exp Res, 2011, Sensation seeking and common and unique variance in conduct disorder and substance misuse.	21039636	10.1111/j.1530-0277.2010.01331.x	Cited
Chassin, L et al., J Stud Alcohol, 1992, Recruiting a community sample of adolescent children of alcoholics: a comparison of three subject sources.	1619925	10.15288/jsa.1992.53.316	Cited
Cohen, P et al., J Child Psychol Psychiatr, 1993, An epidemiological study of disorders in late childhood and adolescence, 1: age- and gender-specific prevalence.	8408371	10.1111/j.1469-7610.1993.tb01094.x	Cited
Comeau, N et al., Addict Behav, 2001, The relations of trait anxiety, anxiety sensitivity, and sensation seeking to adolescents’ motivations for alcohol, cigarette, and marijuana use.	11768546	10.1016/s0306-4603(01)00238-6	Cited
Comings, DE et al., Prog Brain Res, 2000, Reward deficiency syndrome: genetic aspects of behavioral disorders.	11105655	10.1016/S0079-6123(00)26022-6	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
Derefinko, K et al., Aggress Behav, 2011, Do different facets of impulsivity predict different types of aggression?	21259270	10.1002/ab.20387	Cited
Dick, D 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
Dick, DM et al., Addict Biol, 2010, Review: understanding the construct of impulsivity and its relationship to alcohol use disorders.	20148781	10.1111/j.1369-1600.2009.00190.x	Primary
Dick, DM et al., Addict Biol, 2013, Genetic influences on alcohol use across stages of development: GABRA2 and longitudinal trajectories of drunkenness from adolescence to young adulthood.	23692184	10.1111/adb.12066	Primary
Dick, DM et al., Arch Gen Psychiatr, 2009, Role of GABRA2 in trajectories of externalizing behavior across development and evidence of moderation by parental monitoring.	19487630	10.1001/archgenpsychiatry.2009.48	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., J Stud Alcohol Drugs, 2006, Marital status, alcohol dependence, and GABRA2: evidence for gene–environment correlation and interaction.	16562401	10.15288/jsa.2006.67.185	Primary
Dick, DM, Curr Dir Psychol Sci, 2007, Identification of genes influencing a spectrum of externalizing psychopathology.	—	—	—
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
Endicott, J et al., Family history-research diagnostic criteria. Biometrics Research, 1975	—	—	—
Enoch, MA et al., Am J Med Genet B Neuropsychtr Genet, 2006, Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism.	16874763	10.1002/ajmg.b.30336	Cited
Enoch, MA, Pharmacol Biochem Be, 2008, The role of GABAA receptors in the development of alcoholism.	18440057	10.1016/j.pbb.2008.03.007	Cited
Eysenck, SBG et al., Pers Indiv Differ, 1985, Age norms for impulsiveness, venturesomeness and empathy in children.	—	—	—
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
Fendrich, M et al., Drug Alcohol Depend, 2001, Multiwave analysis of retest artifact in the national longitudinal survey of youth drug use.	11295329	10.1016/s0376-8716(00)00177-0	Cited
Fisher, SL et al., Alcohol Clin Exp Res, 2006, Teenagers are right—parents do not know much: an analysis of adolescent-parent agreement on reports of adolescent substance use, abuse, and dependence.	17010137	10.1111/j.1530-0277.2006.00205.x	Primary
Frick, PJ et al., J Clin Child Adolesc Psychol, 2004, Temperament and developmental pathways to conduct problems.	15028541	10.1207/S15374424JCCP3301_6	Cited
Gottesman, II et al., Am J Psychiatry, 2003, The endophenotype concept in psychiatry: etymology and strategic intentions.	12668349	10.1176/appi.ajp.160.4.636	Cited
Handley, ED et al., J Abnorm Psychol, 2011, Do executive and reactive disinhibition mediate the effects of familial substance use disorders on adolescent externalizing outcomes?	21668077	10.1037/a0024162	Cited
Haughey, HM et al., Genes Brain Behav, 2008, The human GABA(A) receptor alpha2 gene moderates the acute effects of alcohol and brain mRNA expression.	18005236	10.1111/j.1601-183X.2007.00369.x	Cited
Hicks, BM et al., JAMA Psychiatr, 2013, Genetic and environmental influences on the familial transmission of externalizing disorders in adoptive and twin offspring.	23965950	10.1001/jamapsychiatry.2013.258	Cited
Hodgkinson, CA, Alcohol Alcohol, 2008, Addictions biology: haplotype-based analysis for 130 candidate genes on a single array.	18477577	10.1093/alcalc/agn032	Cited
Hur, Y et al., Behav Genet, 1997, The genetic correlation between impulsivity and sensation seeking traits.	9336082	10.1023/a:1025674417078	Cited
Johnson, SW et al., J Neurosci, 1992, Opioids excite dopamine neurons by hyperpolarization of local interneurons.	1346804	10.1523/JNEUROSCI.12-02-00483.1992	Cited
Jonas, KG et al., J Abnorm Psychol, 2014, A meta-analytic evaluation of the endophenotype hypothesis: effects of measurement paradigm in the psychiatric genetics of impulsivity.	24978691	10.1037/a0037094	Cited
Kendler, KS et al., Arch Gen Psychiatry, 2008, Genetic and environmental influences on alcohol, caffeine, cannabis, and nicotine use from early adolescence to middle adulthood.	18519825	10.1001/archpsyc.65.6.674	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
Li, D et al., Neuropsychopharmacology, 2014, Association of γ-aminobutyric acid A receptor α2 gene (GABRA2) with alcohol use disorder.	24136292	10.1038/npp.2013.291	Cited
Lind, P 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
Lynam, DR et al., J Quant Criminol, 2004, Personality pathways to impulsive behavior and their relations to deviance: results from three samples.	—	—	—
MacKinnon, DP et al., Multivariate Behav Res, 2004, Confidence limits for the indirect effect: distribution of the product and resampling methods.	20157642	10.1207/s15327906mbr3901_4	Cited
McGue, M et al., Dev Psychol, 1993, Personality stability and change in early adulthood: a behavioral genetic analysis.	—	—	—
Melroy, WE et al., Behav Genet, 2014, Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study.	24687270	10.1007/s10519-014-9653-y	Cited
Miller, DJ et al., J Psychopathol Behav Assess, 2010, Impulsivity and attention deficit-hyperactivity disorder: subtype classification using the UPPS impulsive behavior scale.	21765593	10.1007/s10862-009-9155-z	Cited
Miller, J et al., Personal Individ Differ, 2003, A test of the four-factor model of impulsivity-related traits.	—	—	—
Muthén, LK et al., Mplus User's Guide	—	—	—
O'Connor, TG et al., J Child Psychol Psyc, 1998, Genetic contributions to continuity, change, and co-occurrence of antisocial and depressive symptoms in adolescence.	9670088	—	Cited
Perry, BL et al., Behav Genet, 2013, Gender-specific gene-environment interaction in alcohol dependence: the impact of daily life events and GABRA2.	23974430	10.1007/s10519-013-9607-9	Primary
Philibert, RA et al., Psychiatr Genet, 2009, Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa adoption studies.	19672139	10.1097/YPG.0b013e3283208026	Cited
Pierucci-Lagha, A et al., Neuropsychopharmacology, 2005, GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride.	15702134	10.1038/sj.npp.1300688	Cited
Raine, A, J Abnorm Child Psychol, 2002, Biosocial studies of antisocial and violent behavior in children and adults: a review.	12108763	10.1023/a:1015754122318	Cited
Rhee, SH et al., Arch Gen Psychiatry, 2003, Genetic and environmental influences on substance initiation, use, and problem use in adolescents.	14662558	10.1001/archpsyc.60.12.1256	Cited
Robins, LN et al., Diagnostic interview schedule for the DSMIV (DIS-IV), 2000	—	—	—
Rothbart, MK et al., Handbook of child psychology, vol 3., Social, emotional, personality development, 2006, Temperament.	—	—	—
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
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
Steffensen, SC et al., J Neurosci, 1998, Electrophysiological characterization of GABAergic neurons in the ventral tegmental area.	9742167	10.1523/JNEUROSCI.18-19-08003.1998	Cited
Steinberg, L, Dev Psychobiol, 2010, A dual systems model of adolescent risk-taking.	20213754	10.1002/dev.20445	Cited
Stoltenberg, SF et al., Addiction, 1998, Evaluating measures of family history of alcoholism: density versus dichotomy.	9926555	10.1046/j.1360-0443.1998.931015117.x	Cited
Storey, JD, J R Stat Soc Series B Stat Methodol, 2002, A direct approach to false discovery rates.	—	—	—
Tian, C et al., Hum Mol Genet, 2008, Accounting for ancestry: population substructure and genome-wide association studies.	18852203	10.1093/hmg/ddn268	Cited
Trucco, EM et al., J Child Psychol Psyc, 2014, Rule breaking mediates the developmental association between GABRA2 and adolescent substance abuse.	24811113	10.1111/jcpp.12244	Cited
Uhart, M et al., Addict Biol, 2013, GABRA2 markers moderate the subjective effects of alcohol.	22501025	10.1111/j.1369-1600.2012.00457.x	Cited
Vassos, E et al., Mol Psychiatry, 2014, Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression.	23546171	10.1038/mp.2013.31	Cited
Villafuerte, S et al., Genes Brain Behav, 2013, Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems.	23566244	10.1111/gbb.12039	Cited
Villafuerte, S et al., Mol Psychiatry, 2012, 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
Ward, LD et al., Nucleic Acids Res, 2012, HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants.	22064851	10.1093/nar/gkr917	Cited
Whiteside, SP et al., Pers Individ Dif, 2001, The five factor model and impulsivity: using a structural model of personality to understand impulsivity.	—	—	—
Young, SE et al., Am J Med Genet B Neuropsychiatr Genet, 2000, Genetic and environmental influences on behavioral disinhibition.	11054778	—	Cited
Zucker, RA et al., Ann NY Acad Sci, 1994, Developmental evidence for at least two alcoholisms. I. biopsychosocial variation among pathways into symptomatic difficulty.	8154674	10.1111/j.1749-6632.1994.tb24706.x	Cited
Zuckerman, M, Sensation seeking: beyond the optimal level of arousal, 1979	—	—	—

Title	Year	PMID
A genome wide association study of fast beta EEG in families of European ancestry.	2017	28040410
An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.	2017	28070124

Title	Authors	Journal	Year	Link
Disordered eating in adolescence: the roles of sensation seeking, weight status, and behavioral difficulties.	Bogner M et al.	—	2026	→
Bibliometric Insights in Genetic Factors of Substance-Related Disorders: Intellectual Developments, Turning Points, and Emerging Trends.	Wang K et al.	—	2021	→
A genome wide association study of fast beta EEG in families of European ancestry.	Meyers JL et al.	—	2017	→
An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.	Meyers JL et al.	—	2017	→
Stressful life events increase aggression and alcohol use in young carriers of the GABRA2 rs279826/rs279858 A-allele.	Kiive E et al.	—	2017	→
Predicting substance use in emerging adulthood: A genetically informed study of developmental transactions between impulsivity and family conflict.	Elam KK et al.	—	2016	→

Mechanisms in the relation between GABRA2 and adolescent externalizing problems.

In this knowledge base

External