Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence.
- Authors
- Kuo, Po-Hsiu; Kalsi, Gursharan; Prescott, Carol A; Hodgkinson, Colin A; Goldman, David; Alexander, Jeffry; van den Oord, Edwin J; Chen, Xiangning; Sullivan, Patrick F; Patterson, Diana G; Walsh, Dermot; Kendler, Kenneth S; Riley, Brien P
- Year
- 2009
- Journal
- Drug and alcohol dependence
- PMID
- 19111404
- DOI
- 10.1016/j.drugalcdep.2008.11.009
- PMCID
- PMC2844896
BACKGROUND: The relation of gamma-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417-429]. METHODS: Participants were recruited in Ireland, including 575 independent cases who met DSM-IV AD criteria and 530 controls, screened for heavy drinking. We first conducted case-control analyses of the GAD genes with AD and, within the cases, examined associations with age at onset of AD, withdrawal symptoms, and two quantitative measures: initial sensitivity and tolerance (based on scales from the Self-Rating of the Effects of Ethanol) [Schuckit, M.A., Smith, T.L., Tipp, J.E., 1997. The self-rating of the effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism. Addiction 92, 979-988]. A total of 29 SNPs were genotyped for GAD1 and GAD2 using the Illumina GoldenGate protocols. Statistical procedures were implemented to control for false discovery rates (FDR). RESULTS: Nine of 29 markers with minor allele frequencies less than 0.01 were removed from standard analysis; the remaining 20 markers were all in Hardy-Weinberg equilibrium. Three markers in the intronic regions of GAD1 were associated with initial sensitivity to alcohol (P=0.002); the associations remained significant after a FDR based correction for multiple testing. In addition, one marker located 3kb upstream of GAD1 exhibited association with age at onset of AD (P=0.0001). Gender specific effects were observed in results of both single marker and haplotype analyses. CONCLUSION: We found no evidence for the association of GAD genes with AD but significant association of GAD1 with initial sensitivity and age at onset of AD. Our findings suggest that the underlying pathophysiology regulated by genes like GAD1 may be more directly related to the component processes that form AD than to the clinical disorder.
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| Name | Type |
|---|---|
| AD cases local | cohort |
| addiction | phenotype |
| age at onset | phenotype |
| age at onset of AD local | phenotype |
| Age at onset of AD local | phenotype |
| Age-at-onset of AD local | phenotype |
| Age-at-onset of Alcohol Dependence local | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcoholism | phenotype |
| alcohol preference | phenotype |
| alcohol-related phenotypes | phenotype |
| alcohol-related problems | phenotype |
| alcohol self-administration | phenotype |
| alcohol sensitivity | phenotype |
| Alcohol Use | phenotype |
| Alzheimer's disease | phenotype |
| anxiety-like behavior | phenotype |
| basal GABA levels local | phenotype |
| benzodiazepines | drug |
| Blood level after acute ethanol dose local | phenotype |
| brain | anatomy |
| controls | cohort |
| cortex | anatomy |
| delirium | phenotype |
| diazepam | drug |
| drinking | phenotype |
| early AD age-at-onset local | phenotype |
| epilepsy | phenotype |
| estrogen | drug |
| ethanol consumption | phenotype |
| ethanol dependence | phenotype |
| European–American with AD local | cohort |
| Excitotoxic neuronal death local | phenotype |
| full sample | cohort |
| GABA | phenotype |
| GABAA receptor | drug |
| GABAB receptor | drug |
| GABA receptor agonist local | drug |
| GABA receptor genes | gene |
| GABRA2 | gene |
| Gabra4 | gene |
| GAD1 | gene |
| GAD2 | gene |
| GAD expression level change local | phenotype |
| GAD genes local | gene |
| general population sample | cohort |
| glutamate | drug |
| Han Taiwanese men local | cohort |
| haplotype 1121 local | variant |
| haplotype 1121 (GAD1) local | variant |
| haplotype 2111 local | variant |
| haplotype 2111 (GAD1) local | variant |
| HapMap | cohort |
| hippocampus | anatomy |
| humans | cohort |
| IASPSAD local | cohort |
| IASPSAD families local | cohort |
| IASPSAD family sample local | cohort |
| Initial sensitivity | phenotype |
| Irish cohort local | cohort |
| Irish sample local | cohort |
| kappa opioid receptor agonist local | drug |
| later AD age-at-onset local | phenotype |
| lethal phenotype | phenotype |
| major depressive disorder | phenotype |
| male participants | cohort |
| Male samples local | cohort |
| men | cohort |
| methamphetamine | drug |
| monkeys | cohort |
| murine | cohort |
| neuroactive steroids | drug |
| NMDA receptor | drug |
| normal brain GABA local | phenotype |
| onset | phenotype |
| pentobarbital | drug |
| progesterone | drug |
| Pyridoxal phosphate local | drug |
| Quantitative alcohol-related traits local | phenotype |
| Rare Haplotype local | variant |
| rats | cohort |
| rodents | cohort |
| rs1978340 local | variant |
| rs2058725 local | variant |
| rs2236418 local | variant |
| rs2241165 local | variant |
| rs2839670 local | variant |
| rs2839673 local | variant |
| rs2839677 local | variant |
| rs3791878 local | variant |
| rs3828275 local | variant |
| rs701492 local | variant |
| rs7900976 local | variant |
| Russian males local | cohort |
| Russian males with AD local | cohort |
| Russian men local | cohort |
| Russian sample local | cohort |
| Self-Rating of the Effects of alcohol | phenotype |
| sensitization | phenotype |
| sex | phenotype |
| sex differences | phenotype |
| Subjective response to ethanol local | phenotype |
| synaptosomal GABA release local | phenotype |
| Taiwanese sample local | cohort |
| tolerance | phenotype |
| tolerance/maximum drinking local | phenotype |
| Tolerance/maximum drinking local | phenotype |
| TOLMX local | phenotype |
| U.S. college students with drinking problems local | cohort |
| WDSFS local | phenotype |
| Western European cohort local | cohort |
| withdrawal | phenotype |
| withdrawal severity | phenotype |
| Withdrawal severity factor score local | phenotype |
| women | cohort |
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