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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 SLC6A1 LD structure and recombination hotspots in the 5 populations. Upper graphs illustrate elevations from the background recombination rates across the SLC6A1 gene. Y axis represent recombination rate and X axis represents physical distance between the markers [19, 20]. In Figure A, recombination rates for HapMap CEPH Western Europeans (CEU) and European-Americans of the present study are presented. In Figure B, recombination rates for HapMap Yoruban (YRI) and African-Americans of the present study are presented. In Figure C, recombination rates for HapMap combined Han Chinese and Japanese populations (HCB+JPT) and the Thais of the present study are presented. In Figures D and E, recombination rates for the Finns and Hmongs of the present study are presented. In the middle, the exon-intron structure of SLC6A1 and location of the markers is presented. LD (D') between the SNPs in SLC6A1 is illustrated in the lower triangular graphs.
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Figure 2: Illustration of the SLC6A1 LD structure and recombination hotspots in the 5 populations. Upper graphs illustrate elevations from the background recombination rates across the SLC6A1 gene. Y axis represent recombination rate and X axis represents physical distance between the markers [19, 20]. In Figure A, recombination rates for HapMap CEPH Western Europeans (CEU) and European-Americans of the present study are presented. In Figure B, recombination rates for HapMap Yoruban (YRI) and African-Americans of the present study are presented. In Figure C, recombination rates for HapMap combined Han Chinese and Japanese populations (HCB+JPT) and the Thais of the present study are presented. In Figures D and E, recombination rates for the Finns and Hmongs of the present study are presented. In the middle, the exon-intron structure of SLC6A1 and location of the markers is presented. LD (D') between the SNPs in SLC6A1 is illustrated in the lower triangular graphs.

Mentions: For analysis of linkage disequilibrium in SLC6A1, a total of 16 SNPs were genotyped in the AA, Thai, Hmong, EA, and Finnish samples. The SNPs were selected with the goal of encompassing the SLC6A1 gene with SNPs with allele frequencies > 10% in most populations studied in order to allow comparison of LD patterns between populations. Twelve of the 16 SNPs studied met this criterion. SNP rs1710879 was virtually monomorphic in AA population. The allele frequencies of all 16 SNPs were in Hardy-Weinberg equilibrium (HWE). The LD structure of the SLC6A1 gene, as detected by this set of SNPs, was evaluated by calculating D' and r2 using the HAPLOVIEW program [16]. The LD structure of the SLC6A1 gene is presented in Figure 2. Fragmentation of LD into several poorly-defined blocks was noted in all 5 populations studied (Figure 2). There were two short blocks of LD (D' = 0.8–1) observed in all five populations. The first block is located between the markers -29477 (Marker 1, Figure 2) and -24321 (Marker 2, Figure 2). The second LD block, which is located between markers -17590 (Marker 3, Figure 2) and -9765 (Marker 5, Figure 2), was also found in all populations studied, although the level of LD was lower in AAs. The third LD block was observed in the EA and Finnish populations between markers -1529 (Marker 6, Figure 2) and 3164 (Marker 8, Figure 2).


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 SLC6A1 LD structure and recombination hotspots in the 5 populations. Upper graphs illustrate elevations from the background recombination rates across the SLC6A1 gene. Y axis represent recombination rate and X axis represents physical distance between the markers [19, 20]. In Figure A, recombination rates for HapMap CEPH Western Europeans (CEU) and European-Americans of the present study are presented. In Figure B, recombination rates for HapMap Yoruban (YRI) and African-Americans of the present study are presented. In Figure C, recombination rates for HapMap combined Han Chinese and Japanese populations (HCB+JPT) and the Thais of the present study are presented. In Figures D and E, recombination rates for the Finns and Hmongs of the present study are presented. In the middle, the exon-intron structure of SLC6A1 and location of the markers is presented. LD (D') between the SNPs in SLC6A1 is illustrated in the lower triangular graphs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Illustration of the SLC6A1 LD structure and recombination hotspots in the 5 populations. Upper graphs illustrate elevations from the background recombination rates across the SLC6A1 gene. Y axis represent recombination rate and X axis represents physical distance between the markers [19, 20]. In Figure A, recombination rates for HapMap CEPH Western Europeans (CEU) and European-Americans of the present study are presented. In Figure B, recombination rates for HapMap Yoruban (YRI) and African-Americans of the present study are presented. In Figure C, recombination rates for HapMap combined Han Chinese and Japanese populations (HCB+JPT) and the Thais of the present study are presented. In Figures D and E, recombination rates for the Finns and Hmongs of the present study are presented. In the middle, the exon-intron structure of SLC6A1 and location of the markers is presented. LD (D') between the SNPs in SLC6A1 is illustrated in the lower triangular graphs.
Mentions: For analysis of linkage disequilibrium in SLC6A1, a total of 16 SNPs were genotyped in the AA, Thai, Hmong, EA, and Finnish samples. The SNPs were selected with the goal of encompassing the SLC6A1 gene with SNPs with allele frequencies > 10% in most populations studied in order to allow comparison of LD patterns between populations. Twelve of the 16 SNPs studied met this criterion. SNP rs1710879 was virtually monomorphic in AA population. The allele frequencies of all 16 SNPs were in Hardy-Weinberg equilibrium (HWE). The LD structure of the SLC6A1 gene, as detected by this set of SNPs, was evaluated by calculating D' and r2 using the HAPLOVIEW program [16]. The LD structure of the SLC6A1 gene is presented in Figure 2. Fragmentation of LD into several poorly-defined blocks was noted in all 5 populations studied (Figure 2). There were two short blocks of LD (D' = 0.8–1) observed in all five populations. The first block is located between the markers -29477 (Marker 1, Figure 2) and -24321 (Marker 2, Figure 2). The second LD block, which is located between markers -17590 (Marker 3, Figure 2) and -9765 (Marker 5, Figure 2), was also found in all populations studied, although the level of LD was lower in AAs. The third LD block was observed in the EA and Finnish populations between markers -1529 (Marker 6, Figure 2) and 3164 (Marker 8, Figure 2).

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