title: Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research.
abstract: BACKGROUND
  GABA transporter-1 (GAT-1; genetic locus SLC6A1) is emerging as a novel target for treatment of neuropsychiatric disorders. To understand how population differences might influence strategies for pharmacogenetic studies, we identified patterns of genetic variation and linkage disequilibrium (LD) in SLC6A1 in five populations representing three continental groups.
  
  
  RESULTS
  We resequenced 12.4 kb of SLC6A1, including the promoters, exons and flanking intronic regions in African-American, Thai, Hmong, Finnish, and European-American subjects (total n = 40). LD in SLC6A1 was examined by genotyping 16 SNPs in larger samples. Sixty-three variants were identified through resequencing. Common population-specific variants were found in African-Americans, including a novel 21-bp promoter region variable number tandem repeat (VNTR), but no such variants were found in any of the other populations studied. Low levels of LD and the absence of major LD blocks were characteristic of all five populations. African-Americans had the highest genetic diversity. European-Americans and Finns did not differ in genetic diversity or LD patterns. Although the Hmong had the highest level of LD, our results suggest that a strategy based on the use of tag SNPs would not translate to a major improvement in genotyping efficiency.
  
  
  CONCLUSIONS
  Owing to the low level of LD and presence of recombination hotspots, SLC6A1 may be an example of a problematic gene for association and haplotype tagging-based genetic studies. The 21-bp promoter region VNTR polymorphism is a putatively functional candidate allele for studies focusing on variation in GAT-1 function in the African-American population.
authors.affiliation: Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA. rungnapa.h@student.chula.ac.th
authors.forename: Rungnapa
authors.initials: R
authors.lastname: Hirunsatit
authors.forename: Risto
authors.initials: R
authors.lastname: Ilomäki
authors.forename: Robert
authors.initials: R
authors.lastname: Malison
authors.forename: Pirkko
authors.initials: P
authors.lastname: Räsänen
authors.forename: Essi
authors.initials: E
authors.lastname: Ilomäki
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.forename: Thomas
authors.initials: T
authors.lastname: Kosten
authors.forename: Atapol
authors.initials: A
authors.lastname: Sughondhabirom
authors.forename: Nuntika
authors.initials: N
authors.lastname: Thavichachart
authors.forename: Sookjaroen
authors.initials: S
authors.lastname: Tangwongchai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Listman
authors.forename: Apiwat
authors.initials: A
authors.lastname: Mutirangura
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
mesh_terms: D001741:Black or African American / Q000235:genetics; D000704:Analysis of Variance; D044466:Asian People / Q000235:genetics; D005387:Finland; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D013785:Thailand; D044465:White People / Q000235:genetics
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human