title: GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations.
abstract: BACKGROUND
  Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism.
  
  
  METHODS
  This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag single nucleotide polymorphisms were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs.
  
  
  RESULTS
  We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism, whereas carriers of the IND allele and either rs29220 homozygote were more resilient.
  
  
  CONCLUSIONS
  Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist.
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland.
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Enoch
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland.
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Shen
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland.
authors.forename: Elena
authors.initials: E
authors.lastname: Gorodetsky
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Marietta
authors.affiliation: Psychiatry Service, Department of Veterans Affairs, New Jersey VA Health Care System, East Orange, New Jersey.
authors.forename: Alec
authors.initials: A
authors.lastname: Roy
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005387:Finland; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D065840:Protective Factors; D011804:Quinolines / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics*; D013449:Sulfonamides / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C401824:N-(2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo(4,5-b)pyridin-3-yl)methyl)quinolin-2-yl))trifluoromethanesulfonamide; D011804:Quinolines; D018080:Receptors, GABA-B; C493413:SLC6A1 protein, human; D013449:Sulfonamides
keywords: Alcohol Use Disorders; GABAB Receptor Subunit; GABBR1; GAT1; SLC6A1