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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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This graph illustrates LD span (expressed as median r2) in different populations. Median r2 calculated for SNP pairs in different distance bins (0.1–10 kb, 10.01–20 kb etc) is presented.
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Figure 3: This graph illustrates LD span (expressed as median r2) in different populations. Median r2 calculated for SNP pairs in different distance bins (0.1–10 kb, 10.01–20 kb etc) is presented.

Mentions: In accordance with low levels of LD, Tagger identified few haplotype tagging SNPs [17]. A SNP tagging approach would have allowed omission of three SNPs each in the EA, Finnish, and Thai populations and omission of two SNPs in the Hmong population. None of the 16 SNPs examined in the AA population was identified as a haplotype tagging SNP. We estimated the span of LD in different populations using r2/distance as an index. The index of LD span was about twofold higher in the Hmong population than in any of the other populations. The differences were greatest in the distance bins < 10 kb and 30–40 kb, where the median r2/distance value was two-to-three fold higher in the Hmong than in the other populations (Figure 3).


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)

This graph illustrates LD span (expressed as median r2) in different populations. Median r2 calculated for SNP pairs in different distance bins (0.1–10 kb, 10.01–20 kb etc) is presented.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: This graph illustrates LD span (expressed as median r2) in different populations. Median r2 calculated for SNP pairs in different distance bins (0.1–10 kb, 10.01–20 kb etc) is presented.
Mentions: In accordance with low levels of LD, Tagger identified few haplotype tagging SNPs [17]. A SNP tagging approach would have allowed omission of three SNPs each in the EA, Finnish, and Thai populations and omission of two SNPs in the Hmong population. None of the 16 SNPs examined in the AA population was identified as a haplotype tagging SNP. We estimated the span of LD in different populations using r2/distance as an index. The index of LD span was about twofold higher in the Hmong population than in any of the other populations. The differences were greatest in the distance bins < 10 kb and 30–40 kb, where the median r2/distance value was two-to-three fold higher in the Hmong than in the other populations (Figure 3).

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