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Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research.

Hirunsatit R, Ilomäki R, Malison R, Räsänen P, Ilomäki E, Kranzler HR, Kosten T, Sughondhabirom A, Thavichachart N, Tangwongchai S, Listman J, Mutirangura A, Gelernter J, Lappalainen J - BMC Genet. (2007)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA. rungnapa.h@student.chula.ac.th

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.

Conclusion: 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.

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Illustration of the 21 bp insertion/deletion polymorphism (SLC6A1 long and short alleles) and the insertion/deletion GG allele in the SLC6A1 gene. Picture (A) shows position of -24794 A/G SNP, 21 bp insertion and GG deletion. Picture (B) shows the sequence for the SLC6A1 short and long alleles and the -24794 A/G SNP. The A allele of the -24794 always coincided with the long allele in our populations. Sequence for the GG insertion/deletion polymorphism is presented in picture (C).
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Figure 1: Illustration of the 21 bp insertion/deletion polymorphism (SLC6A1 long and short alleles) and the insertion/deletion GG allele in the SLC6A1 gene. Picture (A) shows position of -24794 A/G SNP, 21 bp insertion and GG deletion. Picture (B) shows the sequence for the SLC6A1 short and long alleles and the -24794 A/G SNP. The A allele of the -24794 always coincided with the long allele in our populations. Sequence for the GG insertion/deletion polymorphism is presented in picture (C).

Mentions: Two novel length polymorphisms were identified in the upper promoter of SLC6A1. The largest, and perhaps the more interesting polymorphism, is a 21-bp VNTR polymorphism, which is present either as a single element or as two tandem repeats, hereafter referred to as the SLC6A1 short and SLC6A1 long allele, respectively. The more common SLC6A1 short allele contains an A/G SNP in its 16th base (-24794 A/G) (Figure 1). In our sample, the A allele of the -24794 SNP is in perfect linkage disequilibrium with the long allele, which contains G in its 16th base. In other words, the A allele always coincides with the long allele.


Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research.

Hirunsatit R, Ilomäki R, Malison R, Räsänen P, Ilomäki E, Kranzler HR, Kosten T, Sughondhabirom A, Thavichachart N, Tangwongchai S, Listman J, Mutirangura A, Gelernter J, Lappalainen J - BMC Genet. (2007)

Illustration of the 21 bp insertion/deletion polymorphism (SLC6A1 long and short alleles) and the insertion/deletion GG allele in the SLC6A1 gene. Picture (A) shows position of -24794 A/G SNP, 21 bp insertion and GG deletion. Picture (B) shows the sequence for the SLC6A1 short and long alleles and the -24794 A/G SNP. The A allele of the -24794 always coincided with the long allele in our populations. Sequence for the GG insertion/deletion polymorphism is presented in picture (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2175509&req=5

Figure 1: Illustration of the 21 bp insertion/deletion polymorphism (SLC6A1 long and short alleles) and the insertion/deletion GG allele in the SLC6A1 gene. Picture (A) shows position of -24794 A/G SNP, 21 bp insertion and GG deletion. Picture (B) shows the sequence for the SLC6A1 short and long alleles and the -24794 A/G SNP. The A allele of the -24794 always coincided with the long allele in our populations. Sequence for the GG insertion/deletion polymorphism is presented in picture (C).
Mentions: Two novel length polymorphisms were identified in the upper promoter of SLC6A1. The largest, and perhaps the more interesting polymorphism, is a 21-bp VNTR polymorphism, which is present either as a single element or as two tandem repeats, hereafter referred to as the SLC6A1 short and SLC6A1 long allele, respectively. The more common SLC6A1 short allele contains an A/G SNP in its 16th base (-24794 A/G) (Figure 1). In our sample, the A allele of the -24794 SNP is in perfect linkage disequilibrium with the long allele, which contains G in its 16th base. In other words, the A allele always coincides with the long allele.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA. rungnapa.h@student.chula.ac.th

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus