Symposium 5, Sunday Sept. 23rd 4 pm–5.30 pm; Room: Lecture Hall 1
Genetics of alcoholism: What's new?: Chairpersons: Preuss UW (Germany), Samochowiec J (Poland)
; |
Abstract |
|---|
Presentation S5-1
Haplotype and TDT analysis at DRD2 locus in families with alcohol dependence
Samochowiec J, Grzywacz A, Kucharska-Mazur J, Pelka-Wysiecka J, Samochowiec A, Finckh U, Rommelspacher H (Poland)
Aims. It is hypothesized that DRD2 is a reinforcement or reward gene. The DRD 2 gene also been implicated in severe alcoholism.
Methods. We examined 85 Polish families (trios) with alcohol dependence according to ICD 10 criteria (age: 34 ± 9). History of alcoholism was obtained using the SSAGA (Polish version). The control subjects (age: 37 ± 19) were 409 ethnically and gender matched, unrelated healthy individuals with excluded psychiatric disorders using Prime MD questionnaire (Primary Care Evaluation of Mental Disorders). Families were analyzed using TDT. Patients were divided into homogenous subgroups with: an early onset of alcoholism (<26 years), withdrawal complicated with delirium or/and seizures, dissocial personality (F 60.2). We studied haplotypes of 3 SNP (-141C ins in promoter, exon 8 A/G, Taq IA) and one STRP in intron 2 of DRD2 gene. SNP were examined by using PCR_RFLP and DNA dinucleotide microsatellite analysis was done using gene scan (ABI 310). Haplotypes were created by 3 SNPs or mentioned 3 SNPs and STRP in intron 2.
Results. TDT and haplotype analysis revealed the protective haplotype I/A1/A/8 in the whole group of patients with alcohol dependence and in subgroup with early onset of alcoholism. Haplotype I/A2/A/7 was transmitted more frequently than expected in families with severe withdrawal complications (seizures and/or delirium).
Conclusions. Haplotype analysis confirmed the role of DRD2 gene in different phenotypes of alcoholism.
Presentation S5-2
Epigenetic findings in alcohol dependence
Lenz B, Bleich S (Germany)
In recent studies we have shown a significant increase of genomic DNA methylation in patients with alcoholism which was significantly associated with their elevated homocysteine levels. Furthermore, we observed a gene specific DNA promoter hypermethylation within the 
synuclein gene and within the HERP promoter. We analysed the DNA promoter methylation of a control gene (presenilin-1) which is known to play no role in addictive disorders. In this gene we could not observe any significant differences of the promoter DNA methylation within the presenilin-1 gene in alcoholics. Since hypermethylation of DNA is an important epigenetic factor in the down regulation of gene expression and since we observed that synuclein is linked to craving which increase is caused by higher allele length of the NACP-REP1 of the synuclein gene, these findings may explain the reduced value of craving under alcohol drinking conditions.
Presentation S5-3
Synaptosomal genes as candidate genes for alcohol dependence and alcoholism related phenotypes
Fehr C, Sander T, Hohmann N, Tadic A, Dahmen N, Anghelescu I, Szegedi A, Lenzen K, Philipps T, Soyka M, Zill P, Preuss UW (Germany)
Aims. Synaptosomal proteins such as syntaxin 1, syntaxin 2, VMAT and Munc-18 play a major role for neurotransmitter synthesis, release and reuptake. Gene expression studies show expression differences of those genes such as the syntaxin binding protein (Stxbp1) or Syntaxin1a between alcohol preferring and alcohol non-preferring mouse strains (Worst et al. 2005, Journal of Neuroscience Research, 80: 529). Within the current study, we tested for association of synaptosomal gene variants and different alcoholism related phenotypes in three different mouse models and two groups of alcohol dependent patients of German origin.
Methods. First, three different crosses of the alcohol preferring (C57/BL6J) and alcohol non-preferring mice strains (DBA/2J) were genotyped for Stxbp1 (Munc-18) gene variants. Second, several SNPs within Stxbp1 were genotyped among two different groups of alcohol dependent patients of German origin and their respective controls.
Results. Molecular variants within Stxbp1 were associated with increased ethanol consume, ethanol preference drinking and ethanol induced hypothermia among the three different mouse models. Human studies confirmed association between variants within Stxbp1 and some markers of alcoholism severity, but not the diagnosis itself.
Conclusions. Mouse and human genetics studies emphasize a role of synaptosomal genes such as Stxbp1 for alcohol drinking and alcohol dependence severity phenotypes.
Presentation S5-4
GABRA2: a risk gene for alcohol dependence?
Preuss U, Fehr C, Koller G, Soyka M, Samochowiec J (Germany)
Aims. Several lines of evidence from animal and human studies indicate that the most important inhibitory neurotransmitter, GABA, plays an important role in alcohol dependence including alcohol withdrawal. The GABAA-receptor, an ion channel, is a pentamer which consists of 5 different subunits. One of these subunits, GABA A2 and its Gene, GABRA2, was identified from linkage analysis to be associated with the liability for alcohol dependence. Subsequent studies in several samples were able to confirm this association. The aim of this study is, to replicate and extent this finding and investigates if genetic variants of the GABRA2 receptor increase the risk for alcoholism-associated phenotypes.
Methods. All together 4 samples of more than 821 inpatient alcohol-dependent of Caucasian descent individuals were analysed into the study. Characteristics of alcohol dependence and alcohol withdrawal were obtained by the SSAGA (Semi-Structured Assessment on Genetics in Alcoholism) or SCID. For all patients and controls, 10 SNPs across GABRA2 were determined using PCR.
Results. Several genetic variants were detected to significantly differ between alcohol-dependent subjects and controls. Common haplotypes and their complementary alleles were identified containing this SNP and were present in the vast majority of the cases and controls and were associated with various alcoholism-related phenotypes.
Conclusions. These findings support and extend the two previous studies implicating the GABA-A receptor as contributing not only to the genetic risk for alcohol dependence but also increase the liability for severe alcohol withdrawal and other characteristics.