Premium
GABBR 1 and SLC 6A1 , Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations
Author(s) -
Enoch MaryAnne,
Hodgkinson Colin A.,
Shen PeiHong,
Gorodetsky Elena,
Marietta Cheryl A.,
Roy Alec,
Goldman David
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12929
Subject(s) - genotype , allele , single nucleotide polymorphism , genetics , phenotype , biology , alcohol dependence , heterozygote advantage , medicine , gene , alcohol , biochemistry
Background Animal and human studies indicate that GABBR 1 , encoding the GABAB 1 receptor subunit, and SLC 6A1, encoding the neuronal gamma‐aminobutyric acid (GABA) transporter GAT 1, 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 GABBR 1 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 SLC 6A1 insertion promoter polymorphism ( IND ) was genotyped in the AA s. Results We found a significant and congruent association between GABBR 1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AA s, Finns) and the major allele in PI s were significantly more common in alcoholics. Moreover, SLC 6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR 1 rs29220 and SLC 6A1 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 GABBR 1 and SLC 6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR 1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist.