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ABSTRACT: The alcohol-preferring (P) and -nonpreferring (NP) rat lines were developed using bidirectional selective breeding for alcohol consumption (g/kg/day) and alcohol preference (water:ethanol ratio). During a preliminary study, we detected a difference in body weight between inbred P (iP) and inbred NP (iNP) rats that appeared to be associated with the transfer of the Chromosome 4 quantitative trait locus (QTL) seen in the P.NP and NP.P congenic strains. After the initial confirmation that iP rats displayed lower body weight when compared to iNP rats (data not shown), body weight and growth rates of each chromosome 4 reciprocal congenic rat strain (P.NP and NP.P) were measured, and their body weight was consistent with their respective donor strain phenotype, confirming that a quantitative trait locus for body weight mapped to the chromosome 4 interval. Utilizing the newly developed interval-specific congenic strains (ISCS-A and ISCS-B), the QTL interval was further narrowed identifying the following candidate genes of interest: neuropeptide Y (Npy), juxtaposed with another zinc finger gene 1 (Jazf1), corticotrophin releasing factor receptor 2 (Crfr2) and LanC lantibiotic synthetase component C-like 2 (Lancl2). These findings indicate that a biologically active variant(s) regulates body weight on rat chromosome 4 in iP and iNP rats. This QTL for body weight was successfully captured in the P.NP and NP.P congenic strains, and interval-specific congenic strains (ISCSs) were subsequently employed to fine-map the QTL interval identifying the following candidate genes of interest: Npy, Jazf1, Crfr2 and Lancl2. Both Npy and Crfr2 have been previously identified as candidate genes of interest underlying the chromosome 4 QTL for alcohol consumption in iP and iNP rats.
Alcohol (Fayetteville, N.Y.) 01/2013; 47(1):63-7. · 2.41 Impact Factor
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ABSTRACT: Ethanol is primarily metabolized in the liver by two rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups.
Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2 were compared in a community sample of Native Americans (n 791) living on reservations and Mexican Americans (n 391) living within the same county.
Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% of the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found.
Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations.
The American Journal of Drug and Alcohol Abuse 09/2012; 38(5):389-94. · 1.55 Impact Factor
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ABSTRACT: BACKGROUND: Prior studies suggest a possible association of a promoter polymorphism in the ALDH1A1 gene ( ALDH1A1*2 ) with alcohol use or dependence. The aim of this study was to examine the association of ALDH1A1*2 with drinking behaviors in Asian young adults and to examine ALDH2 genotype as a potential moderator of these associations. METHODS: Asian young adults (n = 951) were recruited from 2 college sites for studies of genetic associations with alcohol use behavior. Participants completed comprehensive background questionnaires on demographics and drinking behavior. Fingertip blood samples were obtained for DNA extraction and analysis. RESULTS: Participants with the ALDH2*1/*2 genotype reported significantly lower levels (frequency and quantity) of drinking within the last 90 days, fewer numbers of heavy drinking episodes within the last 90 days, and lower lifetime maximum consumption levels compared with ALDH2*1/*1 participants. There were no significant main effects of ALDH1A1*2 on any drinking variables, nor was there a significant interaction between ALDH2 and ALDH1A1 genotypes on drinking outcomes. CONCLUSIONS: The association of ALDH2*2 with reduced alcohol consumption replicates previous findings across numerous studies. Although ALDH1A1*2 was not associated with drinking levels, the lack of an ALDH1A1*2 effect in ALDH2*2 individuals is consistent with the only other study that has examined these associations in East Asian populations.
Alcoholism Clinical and Experimental Research 05/2012; · 3.34 Impact Factor
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ABSTRACT: Dual process models of addiction emphasize the importance of implicit (automatic) cognitive processes in the development and maintenance of substance use behavior. Although genetic influences are presumed to be relevant for dual process models, few studies have evaluated this possibility. The current study examined two polymorphisms with functional significance for alcohol use behavior (COMT Val158Met and ALDH2*2) in relation to automatic alcohol cognitions and tested additive and interactive effects of genotype and implicit cognitions on drinking behavior. Participants were college students (n = 69) who completed Implicit Association Tasks (IATs) designed to assess two classes of automatic drinking motives (enhancement motives and coping motives). Genetic factors did not show direct associations with IAT measures; however, COMT and ALDH2 moderated associations of implicit coping motives with drinking outcomes. Interaction effects indicated that associations of implicit motives with drinking outcomes were strongest in the context of genetic variants associated with relatively higher risk for alcohol use (COMT Met and ALDH2*1). Associations of genotype with drinking behavior were observed for ALDH2 but not COMT. These findings are consistent with the possibility that genetic risk or protective factors could potentiate or mitigate the influence of reflexive cognitive processes on drinking behavior, providing support for the evaluation of genetic influences in the context of dual process models of addiction.
Addiction Biology 02/2011; 17(1):192-201. · 4.83 Impact Factor
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ABSTRACT: We have previously demonstrated that alcohol exposure at early neurulation induces growth retardation, neural tube abnormalities, and alteration of DNA methylation. To explore the global gene expression changes which may underline these developmental defects, microarray analyses were performed in a whole embryo mouse culture model that allows control over alcohol and embryonic variables.
Alcohol caused teratogenesis in brain, heart, forelimb, and optic vesicle; a subset of the embryos also showed cranial neural tube defects. In microarray analysis (accession number GSM9545), adopting hypothesis-driven Gene Set Enrichment Analysis (GSEA) informatics and intersection analysis of two independent experiments, we found that there was a collective reduction in expression of neural specification genes (neurogenin, Sox5, Bhlhe22), neural growth factor genes [Igf1, Efemp1, Klf10 (Tieg), and Edil3], and alteration of genes involved in cell growth, apoptosis, histone variants, eye and heart development. There was also a reduction of retinol binding protein 1 (Rbp1), and de novo expression of aldehyde dehydrogenase 1B1 (Aldh1B1). Remarkably, four key hematopoiesis genes (glycophorin A, adducin 2, beta-2 microglobulin, and ceruloplasmin) were absent after alcohol treatment, and histone variant genes were reduced. The down-regulation of the neurospecification and the neurotrophic genes were further confirmed by quantitative RT-PCR. Furthermore, the gene expression profile demonstrated distinct subgroups which corresponded with two distinct alcohol-related neural tube phenotypes: an open (ALC-NTO) and a closed neural tube (ALC-NTC). Further, the epidermal growth factor signaling pathway and histone variants were specifically altered in ALC-NTO, and a greater number of neurotrophic/growth factor genes were down-regulated in the ALC-NTO than in the ALC-NTC embryos.
This study revealed a set of genes vulnerable to alcohol exposure and genes that were associated with neural tube defects during early neurulation.
BMC Genomics 02/2011; 12:124. · 4.07 Impact Factor
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ABSTRACT: A mechanistic model has been proposed for how alcohol-metabolizing gene variants protect individuals from the development of alcohol use disorders, with heightened sensitivity to alcohol being an early step (endophenotype) in this model. This study was designed to determine whether possession of 2 alcohol-metabolizing genes variations, the aldehyde dehydrogenase ALDH2*2 allele and the alcohol dehydrogenase ADH1B*2 allele, was associated with self-reported sensitivity to alcohol at low doses and at initial use.
Asian-American college students (N=784) of Chinese and Korean descent were genotyped at the ALDH2 and ADH1B loci and assessed for lifetime alcohol symptoms following 1 or 2 drinks and level of response to alcohol during the first 5 lifetime drinking episodes.
Participants who had an ALDH2*2 allele were more likely to report experiencing all 6 low-dose symptoms and having heightened initial response to alcohol. An interaction was found between ALDH2*2 and ADH1B*2, with ADH1B*2 being associated with heightened self-reported sensitivity to alcohol only in individuals who also possessed 1 ALDH2*2 allele.
These findings suggest the effects of ADH1B*2 may be felt more strongly in Asians who already have some heightened sensitivity to alcohol from possessing 1 ALDH2*2 allele, but who are not too sensitized to alcohol from possessing 2 ALDH2*2 alleles. These results offer additional insight into the discrepant findings that have been reported in the literature for the role of ADH1B*2 in response to alcohol and the development of alcohol-related problems.
Alcoholism Clinical and Experimental Research 02/2011; 35(7):1238-45. · 3.34 Impact Factor
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ABSTRACT: Significant evidence has accumulated to suggest an association between single-nucleotide polymorphisms (SNPs) in the GABRA2 gene and alcoholism. However, research has yet to show an association between these polymorphisms and the human brain's reward system function. In this study, we stratified subjects who had participated in an fMRI study of alcohol cue responses according to their genotype at a SNP in GABRA2 (rs279871) shown to be associated with alcohol dependence (Edenberg et al., 2004).
Genotyping showed 13 subjects to be homozygous for the high-risk allele (AA), and 23 subjects to be heterozygous (AG). In fMRI, subjects were exposed to the aromas of their preferred alcoholic drink odors (AO), as well as to appetitive control odors (ApCO) under both alcohol intoxication and placebo control conditions.
Homozygous AA subjects had a larger [AO > ApCO] response than did AG subjects in medial frontal cortical areas thought to code reward value. However, AG subjects had a larger [AO > ApCO] effect in the ventral tegmental area. Alcohol intoxication did not alter these group differences.
These are the first data to suggest that GABRA2 genotype could affect the brain's responses to cues associated with alcohol.
Alcoholism Clinical and Experimental Research 12/2010; 34(12):2169-78. · 3.34 Impact Factor
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ABSTRACT: Background: Significant evidence has accumulated to suggest an association between single-nucleotide polymorphisms (SNPs) in the GABRA2 gene and alcoholism. However, research has yet to show an association between these polymorphisms and the human brain’s reward system function. In this study, we stratified subjects who had participated in an fMRI study of alcohol cue responses according to their genotype at a SNP in GABRA2 (rs279871) shown to be associated with alcohol dependence (Edenberg et al., 2004).Methods: Genotyping showed 13 subjects to be homozygous for the high-risk allele (AA), and 23 subjects to be heterozygous (AG). In fMRI, subjects were exposed to the aromas of their preferred alcoholic drink odors (AO), as well as to appetitive control odors (ApCO) under both alcohol intoxication and placebo control conditions.Results: Homozygous AA subjects had a larger [AO > ApCO] response than did AG subjects in medial frontal cortical areas thought to code reward value. However, AG subjects had a larger [AO > ApCO] effect in the ventral tegmental area. Alcohol intoxication did not alter these group differences.Conclusions: These are the first data to suggest that GABRA2 genotype could affect the brain’s responses to cues associated with alcohol.
Alcoholism Clinical and Experimental Research 11/2010; 34(12):2169 - 2178. · 3.34 Impact Factor
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ABSTRACT: Despite evidence for genetic influences on alcohol use and alcohol-related cognitions, genetic factors and endophenotypes are rarely incorporated in cognitive models of drinking behavior. This study evaluated a model of ALDH2 and drinking behavior stipulating cognitive factors and alcohol sensitivity as accounting for genetic influences on drinking outcomes.
Participants were Asian-American young adults (n = 171) who completed measures of alcohol cognitions (drinking motives, drinking refusal self-efficacy, and alcohol expectancies), alcohol sensitivity, drinking behavior, and alcohol-related problems as part of a prospective study. Structural equation modeling (SEM) evaluated a model of drinking behavior that stipulated indirect effects of ALDH2 on drinking outcomes through cognitive variables and alcohol sensitivity.
The full model provided an adequate fit to the observed data, with the measurement model explaining 63% of the variance in baseline heavy drinking and 50% of the variance in alcohol-related problems at follow-up. Associations of ALDH2 with cognitive factors and alcohol sensitivity were significant, whereas the association of ALDH2 with drinking was not significant with these factors included in the model. Mediation tests indicated significant indirect effects of ALDH2 through drinking motives, drinking refusal self-efficacy, and alcohol sensitivity.
Results are consistent with the perspective that genetic influences on drinking behavior can be partly explained by learning mechanisms and implicate cognitive factors as important for characterizing associations of ALDH2 with drinking.
Alcoholism Clinical and Experimental Research 10/2010; 35(1):91-8. · 3.34 Impact Factor
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ABSTRACT: The high and low alcohol-drinking (HAD and LAD) rats were selectively bred for differences in alcohol intake. The HAD/LAD rats originated from the N/Nih heterogeneous stock developed from intercrossing eight inbred rat strains. The HAD×LAD F2 were genotyped, and a powerful analytical approach, using ancestral recombination and F2 recombination, was used to narrow a quantitative trait loci (QTL) for alcohol drinking to a 2-cM region on distal chromosome 10 that was in common in the HAD1/LAD1 and HAD2/LAD2 analyses. Quantitative real-time PCR was used to examine mRNA expression of six candidate genes (Crebbp, Trap1, Gnptg, Clcn7, Fahd1, and Mapk8ip3) located within the narrowed QTL region in the HAD1/LAD1 rats. Expression was examined in five brain regions, including the nucleus accumbens, amygdala, caudate putamen, hippocampus, and prefrontal cortex. All six genes showed differential expression in at least one brain region. Of the genes tested in this study, Crebbp and Mapk8ip3 may be the most promising candidates with regard to alcohol drinking.
Alcohol (Fayetteville, N.Y.) 09/2010; 44(6):477-85. · 2.41 Impact Factor
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ABSTRACT: There is increasing interest in health interventions that incorporate genetic risk information. Although genetic feedback has been evaluated as an adjunct to smoking cessation interventions, its efficacy for reducing alcohol-related risks is unknown. The purpose of this study was to evaluate the feasibility, acceptability, and efficacy of a web-based alcohol intervention incorporating genetic feedback and risk information specific to ALDH2 genotype. The ALDH2*2 variant is associated with partial protection against alcohol dependence but confers significantly increased risk for alcohol-related cancers as a function of alcohol exposure. Two hundred Asian-American young adults were randomly assigned to receive web-based personalized genetic feedback or attention-control feedback. Genetic feedback included health risk information specific to alcohol-related cancer or alcohol dependence, depending on genotype. Outcomes included postintervention drinking behavior and theoretical correlates of behavior change. Genetic feedback and risk information resulted in significant reductions in 30-day drinking frequency and quantity among participants with the ALDH2*1/*2 genotype. Genetic feedback was rated highly by participants and also showed some effects on theoretical correlates of behavior change. Results provide initial evidence of the feasibility, acceptability, and brief efficacy of web-based genetic feedback for reducing alcohol-related health risks associated with ALDH2 genotype.
Annals of Behavioral Medicine 08/2010; 40(1):77-88. · 4.20 Impact Factor
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ABSTRACT: Selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ greatly in alcohol preference, in part due to a highly significant quantitative trait locus (QTL) on chromosome 4. Alcohol consumption scores of reciprocal chromosome 4 congenic strains NP.P and P.NP correlated with the introgressed interval. The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in five brain regions of alcohol-naïve inbred alcohol-preferring and P.NP congenic rats: amygdala, nucleus accumbens, hippocampus, caudate putamen, and frontal cortex.
Within the QTL region, 104 cis-regulated probe sets were differentially expressed in more than one region, and an additional 53 were differentially expressed in a single region. Fewer trans-regulated probe sets were detected, and most differed in only one region. Analysis of the average expression values across the 5 brain regions yielded 141 differentially expressed cis-regulated probe sets and 206 trans-regulated probe sets. Comparing the present results from inbred alcohol-preferring vs. congenic P.NP rats to earlier results from the reciprocal congenic NP.P vs. inbred alcohol-nonpreferring rats demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in at least one brain region.
Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by consistent results in two independent experiments with reciprocal congenic rats. These genes are strong candidates for affecting alcohol preference in the inbred alcohol-preferring and inbred alcohol-nonpreferring rats.
Genome biology 01/2010; 11(2):R11. · 6.63 Impact Factor
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ABSTRACT: We previously showed that alcohol-preferring (P) rats have higher bone density than alcohol-nonpreferring (NP) rats. Genetic mapping in P and NP rats identified a major quantitative trait locus (QTL) between 4q22 and 4q34 for alcohol preference. At the same location, several QTLs linked to bone density and structure were detected in Fischer 344 (F344) and Lewis (LEW) rats, suggesting that bone mass and strength genes might cosegregate with genes that regulate alcohol preference. The aim of this study was to identify the genes segregating for skeletal phenotypes in congenic P and NP rats. Transfer of the NP chromosome 4 QTL into the P background (P.NP) significantly decreased areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) at several skeletal sites, whereas transfer of the P chromosome 4 QTL into the NP background (NP.P) significantly increased bone mineral content (BMC) and aBMD in the same skeletal sites. Microarray analysis from the femurs using Affymetrix Rat Genome arrays revealed 53 genes that were differentially expressed among the rat strains with a false discovery rate (FDR) of less than 10%. Nine candidate genes were found to be strongly correlated (r(2) > 0.50) with bone mass at multiple skeletal sites. The top three candidate genes, neuropeptide Y (Npy), alpha synuclein (Snca), and sepiapterin reductase (Spr), were confirmed using real-time quantitative PCR (qPCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism involving beta-estradiol, interferon-gamma, and a voltage-gated calcium channel. We identified several candidate genes, including some novel genes on chromosome 4 segregating for skeletal phenotypes in reciprocal congenic P and NP rats.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2010; 25(6):1314-25. · 6.04 Impact Factor
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ABSTRACT: The present study evaluated associations of ALDH2 and ADH1B genotypes with alcohol expectancies and drinking behavior in a sample of Asian American young adults. In addition to assessing global alcohol expectancies, the authors developed a measure of physiological expectancies to evaluate an expectancy phenotype specific to the mechanism by which ALDH2 and ADH1B variations presumably influence drinking behavior. Compared with individuals with the ALDH2*1/*1 genotype, those with the ALDH2*2 allele reported greater negative alcohol expectancies, greater expectancies for physiological effects of alcohol and lower rates of alcohol use. ADH1B was not associated with alcohol expectancies or drinking behavior. Hierarchical models showed that demographic factors, ALDH2 genotype, and expectancy variables explained unique variance in drinking outcomes. Mediation tests showed significant indirect effects of ALDH2 on drinking frequency and peak lifetime consumption through expectancies. These results provide support for influences of genetic factors and alcohol sensitivity on alcohol-related learning and suggest the importance of developing biopsychosocial models of drinking behavior in Asian Americans.
Psychology of Addictive Behaviors 09/2009; 23(3):452-63. · 2.09 Impact Factor
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ABSTRACT: The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hours after the last drinking episode, rats were euthanized, the brains extracted, and the ACB dissected. RNA was extracted and purified for microarray analysis. The only significant differences were between the CA and W groups (p<0.01; Storey false discovery rate=0.15); there were 374 differences in named genes between these 2 groups. There were 20 significant Gene Ontology (GO) categories, which included negative regulation of protein kinase activity, anti-apoptosis, and regulation of G-protein coupled receptor signaling. Ingenuity analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression in the ACB of the CA group), suggesting increased neuronal activity. There were 43 genes located within rat QTLs for alcohol consumption and preference; 4 of these genes (Tgfa, Hspa5, Mtus1 and Creb3l2) are involved in anti-apoptosis and increased transcription, suggesting that they may be contributing to cellular protection and maintaining high alcohol intakes. Overall, these findings suggest that chronic CA drinking results in genomic changes that can be observed during the early acute phase of ethanol withdrawal. Conversely, chronic MSA drinking, with its associated protracted withdrawal periods, results in genomic changes that may be masked by tight regulation of these genes following repeated experiences of ethanol withdrawal.
Pharmacology Biochemistry and Behavior 09/2009; 94(1):131-47. · 2.53 Impact Factor
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ABSTRACT: This paper reports the identification of a novel cytosolic aldehyde dehydrogenase 1 ( ALDH1A1 ) allele. One hundred and sixty-two Indo-Trinidadian and 85 Afro-Trinidadian individuals were genotyped. A novel ALDH1A1 allele, ALDH1A1*4 , was identified in an Indo-Trinidadian alcoholic with an A inserted at position -554 relative to the translational start site, +1. It was concluded that a wider cross-section of individuals needs to be evaluated in order to determine the representative frequency of the allele, and to see if it is associated with risk of alcoholism.
Human genomics 08/2009; 3(4):304-7.
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ABSTRACT: A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), alpha-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.
Current Drug Abuse Reviews 06/2009; 2(2):127-34.
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ABSTRACT: Associations of ALDH2 and ADH1B genotypes with alcohol use have been evaluated largely using case-control studies, which typically focus on adult samples and dichotomous diagnostic outcomes. Relatively fewer studies have evaluated ALDH2 and ADH1B in relation to continuous drinking outcomes or at different developmental stages. This study examined additive and interactive effects of ALDH2 and ADH1B genotypes on drinking behavior in a mixed-gender sample of Asian young adults, focusing on continuous phenotypes (e.g., heavy episodic and hazardous drinking, alcohol sensitivity, drinking consequences) whose expression is expected to precede the onset of alcohol use disorders.
The sample included 182 Chinese- and Korean-American young adults ages 18 years and older (mean age = 20 years). Effects of ALDH2, ADH1B and ethnicity were estimated using generalized linear modeling.
The ALDH2*2 allele predicted lower reported rates of alcohol use and drinking consequences as well as greater reported sensitivity to alcohol. There were significant ethnic group differences in drinking outcomes, such that Korean ethnicity predicted higher drinking rates and lower alcohol sensitivity. ADH1B status was not significantly related to drinking outcomes.
Ethnicity and ALDH2 status, but not ADH1B status, consistently explained significant variance in alcohol consumption in this relatively young sample. Results extend previous work by showing an association of ALDH2 genotype with drinking consequences. Findings are discussed in the context of possible developmental and population differences in the influence of ALDH2 and ADH1B variations on alcohol-related phenotypes.
Alcoholism Clinical and Experimental Research 04/2009; 33(5):839-47. · 3.34 Impact Factor
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Leah Wetherill,
Marc A Schuckit,
Victor Hesselbrock,
Xiaoling Xuei, Tiebing Liang,
Danielle M Dick,
John Kramer,
John I Nurnberger,
Jay A Tischfield,
Bernice Porjesz,
Howard J Edenberg,
Tatiana Foroud
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ABSTRACT: Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression.
A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic families of European American descent recruited as part of the Collaborative Studies on the Genetics of Alcoholism (COGA) study. Family-based association analysis was performed to test the primary hypothesis that variation in these genes is associated with alcohol dependence. Secondary analyses evaluated whether there was an association of these SNPs with symptoms of alcohol withdrawal, cocaine dependence, or comorbid alcohol and cocaine dependence.
Although variations in NPY itself were not associated with these phenotypes, variations in 2 NPY-receptor genes were. SNPs in NPY2R provided significant evidence of association with alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence (all p < 0.03). Haplotype analyses strengthened the evidence for these phenotypes (global 0.0004 < p < 0.005). SNPs in NPY5R demonstrated significant association with alcohol withdrawal characterized by seizures (p < 0.05).
These results indicate that sequence variations in NPY receptor genes are associated with alcohol dependence, particularly a severe subtype of alcohol dependence characterized by withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.
Alcoholism Clinical and Experimental Research 10/2008; 32(12):2031-40. · 3.34 Impact Factor
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ABSTRACT: The current study examined the effects of operant ethanol (EtOH) self-administration on gene expression kin the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-preferring (iP) rats. Rats self-trained on a standard two-lever operant paradigm to administer either water-water, EtOH (15% v/v)-water, or saccharin (SAC; 0.0125% g/v)-water. Animals were killed 24 h after the last operant session, and the ACB and AMYG dissected; RNA was extracted and purified for microarray analysis. For the ACB, there were 513 significant differences at the p<0.01 level in named genes: 55 between SAC and water; 215 between EtOH and water, and 243 between EtOH and SAC. In the case of the AMYG (p<0.01), there were 48 between SAC and water, 23 between EtOH and water, and 63 between EtOH and SAC group. Gene Ontology (GO) analysis indicated that differences in the ACB between the EtOH and SAC groups could be grouped into 15 significant (p<0.05) categories, which included major categories such as synaptic transmission, cell and ion homeostasis, and neurogenesis, whereas differences between the EtOH and water groups had only 4 categories, which also included homeostasis and synaptic transmission. Several genes were in common between the EtOH and both the SAC and water groups in the synaptic transmission (e.g., Cav2, Nrxn3, Gabrb2, Gad1, Homer1) and homeostasis (S100b, Prkca, Ftl1) categories. Overall, the results suggest that changes in gene expression in the ACB of iP rats are associated with the reinforcing effects of EtOH.
Pharmacology Biochemistry and Behavior 07/2008; 89(4):481-98. · 2.53 Impact Factor
