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‣ Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

DIXON, Claire I.; MORRIS, Hannah V.; BREEN, Gerome; DESRIVIERES, Sylvane; JUGURNAUTH, Sarah; STEINER, Rebecca C.; VALLADA, Homero; GUINDALINI, Camila; LARANJEIRA, Ronaldo; MESSAS, Guilherme; ROSAHL, Thomas W.; ATACK, John R.; PEDEN, Dianne R.; BELELLI, De
Fonte: NATL ACAD SCIENCES Publicador: NATL ACAD SCIENCES
Tipo: Artigo de Revista Científica
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Because GABA(A) receptors containing alpha 2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha 2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine`s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of alpha 2-GABA(A) receptors (alpha 2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In alpha 2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha 2-GABA(A) receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction...

‣ A Sequence-Ready BAC Contig of the GABAA Receptor Gene Cluster Gabrg1–Gabra2–Gabrb1 on Mouse Chromosome 5

Lengeling, Andreas; Wiltshire, Tim; Otmani, Chris; Bućan, Maja
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /08/1999 Português
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The type-A receptors for the neurotransmitter GABA (γ-aminobutyric acid) are ligand-gated chloride channels that mediate postsynaptic inhibition. The functional diversity of these receptors comes from the use of a large repertoire of subunits encoded by separate genes, as well as from differences in subunit composition of individual receptors. In mammals, a majority of GABAA receptor subunit genes are located in gene clusters that may be important for their regulated expression and function. We have established a high-resolution physical map of the cluster of genes encoding GABAA receptor subunits α2 (Gabra2), β1 (Gabrb1), and γ1 (Gabrg1) on mouse chromosome 5. Rat cDNA probes and specific sequence probes for all three GABAA receptor subunit genes have been used to initiate the construction of a sequence-ready contig of bacterial artificial chromosomes (BACs) encompassing this cluster. In the process of contig construction clones from 129/Sv and C57BL/6J BAC libraries were isolated. The assembled 1.3-Mb contig, consisting of 45 BACs, gives five- to sixfold coverage over the gene cluster and provides an average resolution of one marker every 32 kb. A number of BAC insert ends were sequenced, generating 30 new sequence tag sites (STS) in addition to 6 Gabr gene-based and 3 expressed sequence tag (EST)-based markers. STSs from...

‣ Variations in GABRA2, Encoding the α2 Subunit of the GABAA Receptor, Are Associated with Alcohol Dependence and with Brain Oscillations

Edenberg, Howard J.; Dick, Danielle M.; Xuei, Xiaoling; Tian, Huijun; Almasy, Laura; Bauer, Lance O.; Crowe, Raymond R.; Goate, Alison; Hesselbrock, Victor; Jones, Kevin; Kwon, Jennifer; Li, Ting-Kai; Nurnberger, Jr., John I.; O’Connor, Sean J.; Reich,
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13–28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABAA receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABAA receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3′ end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism...

‣ Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism

Ma, D. Q.; Whitehead, P. L.; Menold, M. M.; Martin, E. R.; Ashley-Koch, A. E.; Mei, H.; Ritchie, M. D.; DeLong, G. R.; Abramson, R. K.; Wright, H. H.; Cuccaro, M. L.; Hussman, J. P.; Gilbert, J. R.; Pericak-Vance, M. A.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis—with the pedigree disequilibrium test and the family-based association test—and for genotypic and haplotypic association analysis—with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test...

‣ GABRG1 and GABRA2 as Independent Predictors for Alcoholism in Two Populations

Enoch, Mary-Anne; Hodgkinson, Colin A.; Yuan, Qiaoping; Albaugh, Bernard; Virkkunen, Matti; Goldman, David
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The chromosome 4 cluster of GABAA receptor genes is predominantly expressed in the brain reward circuitry and this chromosomal region has been implicated in linkage scans for alcoholism. Variation in one chromosome 4 gene, GABRA2, has been robustly associated with alcohol use disorders (AUD) although no functional locus has been identified. Since HapMap data reveals moderate long-distance linkage disequilibrium across GABRA2 and the adjacent gene, GABRG1, it is possible that the functional locus is in GABRG1. We genotyped 24 SNPs across GABRG1 and GABRA2 in two population isolates: 547 Finnish Caucasian men (266 alcoholics) and 311 community-derived Plains Indian men and women (181 alcoholics). In both the Plains Indians and the Caucasians: (a) the GABRG1 haplotype block(s) did not extend to GABRA2; (b) GABRG1 haplotypes and SNPs were significantly associated with AUD; (c) there was no association between GABRA2 haplotypes and AUD; (d) there were several common (≥ 0.05) haplotypes that spanned GABRG1 and GABRA2 (341 kb), three of which were present in both populations: one of these ancestral haplotypes was associated with AUD, the other two were more common in non-alcoholics; this association was determined by GABRG1; (e) in the Finns...

‣ Inter-population linkage disequilibrium (LD) patterns of GABRA2 and GABRG1 genes at the GABA cluster locus on human chromosome 4

Ittiwut, Chupong; Listman, Jennifer; Mutirangura, Apiwat; Malison, Robert; Covault, Jonathan; Kranzler, Henry R.; Sughondhabirom, Atapol; Thavichachart, Nuntika; Gelernter, Joel
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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GABRA2and GABRG1, which encode the α2 and γ1 subunits, respectively, of the GABA-A receptor, are located in a cluster on chromosome 4p. The GABRA2 locus has been found to be associated with alcohol dependence (AD) in several studies, but no functional variant that can account for this association has been identified. In order to understand the reported associations, we sought to understand LD patterns and haplotype structure of these genes. With close intergenic distance, ~90 kb, it was anticipated some markers might show intergenic LD. Variation in 13-SNP haplotype block structure was observed in 5 different populations: European American, African American, Chinese [Han and Thai], Thai, and Hmong. In Hmong, a 280 kb region of considerably higher LD spans the intergenic region, whereas in other populations, there were two or more LD blocks cross this region. These findings may aid in understanding genetic association of this locus with alcohol dependence in several populations.

‣ Markers in the 5′ Region of GABRG1 Associate to Alcohol Dependence and are in Linkage Disequilibrium with Markers in the Adjacent GABRA2 Gene

Covault, Jonathan; Gelernter, Joel; Jensen, Kevin; Anton, Raymond; Kranzler, Henry R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Following an initial report, there have been multiple replications of an association of alcohol dependence (AD) to markers within a haplotype block that includes the 3′-half of the gene encoding the GABAA α-2 subunit (GABRA2), on chromosome 4p. We examined the intergenic extent of this haplotype block and the association to AD of markers in the adjacent 5′ haplotype block in GABRG1, which encodes the GABAA receptor γ-1 subunit. We genotyped 15 SNPs in the GABRG1-GABRA2 interval as well as at 34 ancestry informative markers in three samples: 435 AD and 635 screened control subjects from Connecticut and 812 participants from a multi-center AD treatment trial. We observed two large haplotype blocks in the GABRG1-GABRA2 intergenic interval with a region of increased recombination midway between the two genes. Markers in the two haplotype blocks were in moderate linkage disequilibrium. Compared with markers in the GABRA2 haplotype block, markers in the 5′ GABRG1 haplotype showed greater allelic, genotypic, and haplotypic association with AD in European Americans from both AD samples. Logistic regression analysis indicated that genetic elements in the GABRG1 haplotype block likely contribute to AD risk in an additive fashion while those in the GABRA2 haplotype block may act in a dominant fashion in relation to risk of AD.

‣ 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

Sakai, Joseph T.; Stallings, Michael C.; Crowley, Thomas J.; Gelhorn, Heather L.; McQueen, Matthew B.; Ehringer, Marissa A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. We sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents.

‣ A genome-wide association study of alcohol dependence

Bierut, Laura J.; Agrawal, Arpana; Bucholz, Kathleen K.; Doheny, Kimberly F.; Laurie, Cathy; Pugh, Elizabeth; Fisher, Sherri; Fox, Louis; Howells, William; Bertelsen, Sarah; Hinrichs, Anthony L.; Almasy, Laura; Breslau, Naomi; Culverhouse, Robert C.; Dick
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10−5, but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor α2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

‣ Obesity, Smoking, and Frontal Brain Dysfunction

Bauer, Lance; Dick, Danielle; Bierut, Laura; Bucholz, Kathleen; Edenberg, Howard; Kuperman, Samuel; Kramer, John; Nurnberger, John; O’Connor, Sean; Rice, John; Rohrbaugh, John; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Hesselbrock, Victor
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2010 Português
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Obesity, smoking, and conduct problems have all been associated with decrements in brain function. However, their additive and interactive effects have rarely been examined. To address the deficiency, we studied P300a and P300b electroencephalographic potentials in 218 women grouped by the presence versus absence of: (1) a BMI ≥30 kg/m2; (2) recent smoking; and (3) ≥2 childhood conduct problems. Analyses revealed smaller P300a and P300b amplitudes over the posterior scalp among recent smokers versus nonsmokers. No corresponding group differences were found in P300 latencies or frontal scalp amplitudes. The most interesting analysis result was an interaction between conduct problems and obesity limited to the frontally-generated P300a component: its latency was significantly greater in women with both attributes than in those with either or neither attribute. An exploratory ANOVA, substituting the genotype of a GABRA2 SNP for conduct problems, also demonstrated the interaction. It is hypothesized that conduct problems, and a conduct-problem-associated GABRA2 genotype, decrease the age-of-onset and/or increase the lifetime duration of obesity. As a result, they may potentiate the adverse effects of obesity on frontal white matter and thereby increase P300a latency. Smoking may affect brain function by a different mechanism to reduce posterior scalp P300a and P300b amplitudes while preserving frontal scalp P300a latency and amplitude.

‣ Components of Cross-Frequency Modulation in Health and Disease

Allen, Elena A.; Liu, Jingyu; Kiehl, Kent A.; Gelernter, Joel; Pearlson, Godfrey D.; Perrone-Bizzozero, Nora I.; Calhoun, Vince D.
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
Publicado em 14/07/2011 Português
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The cognitive deficits associated with schizophrenia are commonly believed to arise from the abnormal temporal integration of information, however a quantitative approach to assess network coordination is lacking. Here, we propose to use cross-frequency modulation (cfM), the dependence of local high-frequency activity on the phase of widespread low-frequency oscillations, as an indicator of network coordination and functional integration. In an exploratory analysis based on pre-existing data, we measured cfM from multi-channel EEG recordings acquired while schizophrenia patients (n = 47) and healthy controls (n = 130) performed an auditory oddball task. Novel application of independent component analysis (ICA) to modulation data delineated components with specific spatial and spectral profiles, the weights of which showed covariation with diagnosis. Global cfM was significantly greater in healthy controls (F1,175 = 9.25, P < 0.005), while modulation at fronto-temporal electrodes was greater in patients (F1,175 = 17.5, P < 0.0001). We further found that the weights of schizophrenia-relevant components were associated with genetic polymorphisms at previously identified risk loci. Global cfM decreased with copies of 957C allele in the gene for the dopamine D2 receptor (r = −0.20...

‣ Impulsiveness and Insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism

Villafuerte, Sandra; Heitzeg, Mary M.; Foley, Sara; Yau, Wai-Ying Wendy; Majczenko, Karen; Zubieta, Jon-Kar; Zucker, Robert A.; Burmeister, Margit
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory gamma-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI).

‣ Cerebellum volume in high-risk offspring from multiplex alcohol dependence families: Association with allelic variation in GABRA2 and BDNF

Hill, Shirley Y.; Wang, Shuhui; Carter, Howard; Tessner, Kevin; Holmes, Brian; McDermott, Michael; Zezza, Nicholas; Stiffler, Scott
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence (AD) and related substance use disorders. Greater susceptibility for developing these disorders may be related to structural differences in brain circuits that influence the salience of rewards or modify the efficiency of information processing and AD susceptibility. We examined the cerebellum of 71 adolescent/young adult high-risk (HR) offspring from families with multiple cases of alcohol dependence (multiplex families), and 60 low-risk (LR) controls with no family history of alcohol or drug dependence who were matched for age, gender, socioeconomic status and IQ, with attention given to possible effects of personal use of substances and maternal use during pregnancy. Magnetic resonance images were acquired on a General Electric 1.5-Tesla scanner and manually traced (BRAINS2) blind to clinical information. GABRA2 and BDNF variation were tested for their association with cerebellar volumes. High-risk offspring from multiplex AD families showed greater total volume of the cerebellum and total gray matter (GM), in comparison with LR controls. An interaction between allelic variation in GABRA2 and BDNF genes was associated with GM volumes...

‣ Deletion of the gabra2 Gene Results in Hypersensitivity to the Acute Effects of Ethanol but Does Not Alter Ethanol Self Administration

Dixon, Claire I.; Walker, Sophie E.; King, Sarah L.; Stephens, David N.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 24/10/2012 Português
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Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABAA α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABAA α2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol’s rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates...

‣ The Role of GABRA2 on risk for Alcohol, Nicotine and Cannabis Dependence in the Iowa Adoption Studies

Philibert, Robert A.; Gunter, Tracy D.; Beach, Steven R. H.; Brody, Gene H.; Hollenbeck, Nancy; Andersen, Allan; Adams, William
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/2009 Português
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A number of studies have demonstrated that genetic variation at GABRA2 alters vulnerability to alcohol dependence. However, the exact identity of the causal variant(s), the relationship of these variants to other forms of substance use and behavioral illness is uncertain. Therefore, we genotyped 516 subjects from the Iowa Adoption Studies, a large longitudinal case and control adoption study of substance use, at 39 single nucleotide polymorphisms encompassing the GABRA2 locus and analyzed them with respect to their lifetime history of three common forms of substance use (alcohol (AD), nicotine (ND) and cannabis dependence (CD)), major depressive disorder (MDD) and antisocial personality disorder (ASPD) and relevant exposure variables. Using regression analysis, we found substantial evidence that both GABRA2 genotype and haplotype are significantly related to vulnerability to AD, ND and CD with the strongest relationships noted with respect to ND. Consistent with prior studies suggesting exposure is an important step in the development of substance use, we found the inclusion of substance exposure data in to our analytic models markedly increased the strength of the genetic associations of GABRA2 haplotype with substance use. Finally...

‣ Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems

Villafuerte, Sandra; Strumba, Viktorya; Stoltenberg, Scott F.; Zucker, Robert A.; Burmeister, Margit
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Genetic variants in GABRA2 have previously been shown to be associated with alcohol measures, EEG β waves, and impulsiveness-related traits. Impulsiveness is a behavioral risk factor for alcohol and other substance abuse. Here, we tested association between 11 variants in GABRA2 with NEO- impulsiveness and problem drinking. Our sample of 295 unrelated adult subjects was from a community of families with at least one male with DSM-IV Alcohol use diagnosis, and from a socioeconomically comparable control group.

‣ A GABRA2 Variant Is Associated with Increased Stimulation and ‘High’ Following Alcohol Administration

Arias, Albert J.; Covault, Jonathan; Feinn, Richard; Pond, Timothy; Yang, Bao-Zhu; Ge, Wenjing; Oncken, Cheryl; Kranzler, Henry R.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Aims: Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA α-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4. Methods: Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1. Results: Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure...

‣ Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions

Drgon, Tomas; D’Addario, Claudio; Uhl, George R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 05/12/2006 Português
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Strong genetic contributions to individual differences in vulnerability to addictions are well supported by classical genetic studies. Linkage and association genome scans for addiction vulnerability have provided converging evidence for several chromosomal regions which are likely to harbor allelic variants that contribute to such vulnerability. We and others have delineated a candidate addiction-associated chromosome 4p12 “rSA3” region based on convergent data from association genome scanning studies in polysubstance abusers (Uhl and others 2001), linkage based studies in alcoholism (Long and others 1998; Reich and others 1998) and association-based studies for alcoholism and association-based studies for individual differences in electroencephalographic (EEG) spectral power phenotypes (Edenberg and others 2004; Porjesz and others 2002). The rSA3 region contains interesting candidate genes that encode the alpha 2, alpha 4, beta 1 and gamma 1 receptor subunits for the principal brain inhibitory neurotransmitter, GABA (Covault and others 2004; Edenberg and others 2004; Lappalainen and others 2005). We now report assessment of single nucleotide polymorphism (SNP) genotypes in this region in three samples of substance abusers and controls. These results delineate the haplotypes and patterns of linkage disequilibrium in this region...

‣ Gender-Specific Gene–Environment Interaction in Alcohol Dependence: The Impact of Daily Life Events and GABRA2

Perry, Brea L.; Pescosolido, Bernice A.; Bucholz, Kathleen; Edenberg, Howard; Kramer, John; Kuperman, Samuel; Schuckit, Marc Alan; Nurnberger, John I.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Gender-moderated gene–environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multilevel regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women’s distinct patterns of association.

‣ Dimensional Anxiety Mediates Linkage of GABRA2 Haplotypes With Alcoholism

Enoch, Mary-Anne; Schwartz, Lori; Albaugh, Bernard; Virkkunen, Matti; Goldman, David
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 05/09/2006 Português
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The GABAAα2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite-configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns...