title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Taiwan. pkuo@mail.ncku.edu.tw
authors.forename: Po-Hsiu
authors.initials: PH
authors.lastname: Kuo
authors.forename: Gursharan
authors.initials: G
authors.lastname: Kalsi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Prescott
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Jeffry
authors.initials: J
authors.lastname: Alexander
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: van den Oord
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.forename: Diana G
authors.initials: DG
authors.lastname: Patterson
authors.forename: Dermot
authors.initials: D
authors.lastname: Walsh
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.forename: Brien P
authors.initials: BP
authors.lastname: Riley
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000428:Alcohol Drinking / Q000453:epidemiology* / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D005190:Family; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2