GABBR1and SLC6A1, Two Genes Involved in Modulation of GABASynaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations

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. 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 GABBR1tag single nucleotide polymorphisms were genotyped in the AAand Finnish samples; rs29220 was genotyped in the PIfor replication. Also, a uniquely African, functional SLC6A1insertion promoter polymorphism (IND) was genotyped in the AAs. We found a significant and congruent association between GABBR1rs29220 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 INDwas more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1rs29220 and SLC6A1 INDgenotypes showed that rs29220 heterozygotes, irrespective of their INDstatus, had an increased risk for alcoholism, whereas carriers of the INDallele and either rs29220 homozygote were more resilient. Our results show that with both GABBR1and SLC6A1,the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1rs29220 might predict treatment response/adverse effects for baclofen, a GABABreceptor agonist. The GABBR1gene, encoding the GABAB1 receptor subunit, modulates synaptic GABA thereby playing a role in addiction. We found a congruent association between a GABBR1SNP rs29220 and alcoholism in three populations that differed by alcoholism phenotype and by ethnicity: African Americans (AA), Finnish Caucasians and Plains American Indians (PI). The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. In contrast, the minor genotypes/allele were protective against risk for alcoholism.