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Haplotypic analysis of the TNF locus by association efficiency and entropy.

Ackerman H, Usen S, Mott R, Richardson A, Sisay-Joof F, Katundu P, Taylor T, Ward R, Molyneux M, Pinder M, Kwiatkowski DP - Genome Biol. (2003)

Bottom Line: We found 32 different haplotypes, of which 13 were shared between the two populations.We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure.The most informative subset of SNPs to genotype differs between the two populations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wellcome Trust for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. ackerman@fas.harvard.edu

ABSTRACT

Background: To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and population-based reconstruction methods.

Results: We found 32 different haplotypes, of which 13 were shared between the two populations. Both populations were haplotypically diverse (gene diversity = 0.80, Gambia; 0.85, Malawi) and significantly differentiated (p < 10-5 by exact test). More than a quarter of marker pairs showed evidence of intragenic recombination (29% Gambia; 27% Malawi). We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure. AEA revealed that many SNPs in TNF are poor markers of each other. The EMM showed that 8 of 12 SNPs (Gambia) and 7 of 12 SNPs (Malawi) are required to describe 95% of the haplotypic diversity.

Conclusions: The TNF locus in the Gambian and Malawi sample is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNF SNPs must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.

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Association efficiency and linkage disequilibrium parameters for 12 SNPs at the TNF locus. (a) AEA, Gambia; (b) AEA, Malawi; (c) linkage disequilibrium, Gambia; (d) linkage disequilibrium, Malawi. The apparent relative risk at the marker allele indicated in the leftmost column is given when the hypothetical disease allele indicated in the bottom row is assigned a relative risk of 10. In (a,b) color indicates the magnitude of the apparent relative risk: blue indicates a relative risk of less than twofold, yellow between two- and fourfold, and red between fourfold and the maximum of 10-fold. In (c,d) red indicates p < 0.05 by the chi-squared test, uncorrected for multiple tests.
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Figure 4: Association efficiency and linkage disequilibrium parameters for 12 SNPs at the TNF locus. (a) AEA, Gambia; (b) AEA, Malawi; (c) linkage disequilibrium, Gambia; (d) linkage disequilibrium, Malawi. The apparent relative risk at the marker allele indicated in the leftmost column is given when the hypothetical disease allele indicated in the bottom row is assigned a relative risk of 10. In (a,b) color indicates the magnitude of the apparent relative risk: blue indicates a relative risk of less than twofold, yellow between two- and fourfold, and red between fourfold and the maximum of 10-fold. In (c,d) red indicates p < 0.05 by the chi-squared test, uncorrected for multiple tests.

Mentions: Consistent with the evidence for recombination, linkage disequilibrium is variable across the TNF locus (Figure 4c,4d) and generally low. Values of pairwise linkage disequilibrium, r2, are different between the two populations, though well correlated (r = 0.83). In The Gambia, 80% of SNP pairs have the minor alleles in the repulsion phase, while in Malawi, 65% of SNP pairs are in the repulsion phase. Most of the SNP pairs in the repulsion phase have very low linkage disequilibrium (r2 = 0). There are six pairs of SNPs that are in the coupling phase in the Malawian sample, but are in the repulsion phase in The Gambian sample, reversing the allelic associations. Most of these occasions involve the TNF-244A allele, which is found on only one haplotype in the Gambia (in phase with the TNF-3025G allele), but on five different haplotypes in Malawi.


Haplotypic analysis of the TNF locus by association efficiency and entropy.

Ackerman H, Usen S, Mott R, Richardson A, Sisay-Joof F, Katundu P, Taylor T, Ward R, Molyneux M, Pinder M, Kwiatkowski DP - Genome Biol. (2003)

Association efficiency and linkage disequilibrium parameters for 12 SNPs at the TNF locus. (a) AEA, Gambia; (b) AEA, Malawi; (c) linkage disequilibrium, Gambia; (d) linkage disequilibrium, Malawi. The apparent relative risk at the marker allele indicated in the leftmost column is given when the hypothetical disease allele indicated in the bottom row is assigned a relative risk of 10. In (a,b) color indicates the magnitude of the apparent relative risk: blue indicates a relative risk of less than twofold, yellow between two- and fourfold, and red between fourfold and the maximum of 10-fold. In (c,d) red indicates p < 0.05 by the chi-squared test, uncorrected for multiple tests.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: Association efficiency and linkage disequilibrium parameters for 12 SNPs at the TNF locus. (a) AEA, Gambia; (b) AEA, Malawi; (c) linkage disequilibrium, Gambia; (d) linkage disequilibrium, Malawi. The apparent relative risk at the marker allele indicated in the leftmost column is given when the hypothetical disease allele indicated in the bottom row is assigned a relative risk of 10. In (a,b) color indicates the magnitude of the apparent relative risk: blue indicates a relative risk of less than twofold, yellow between two- and fourfold, and red between fourfold and the maximum of 10-fold. In (c,d) red indicates p < 0.05 by the chi-squared test, uncorrected for multiple tests.
Mentions: Consistent with the evidence for recombination, linkage disequilibrium is variable across the TNF locus (Figure 4c,4d) and generally low. Values of pairwise linkage disequilibrium, r2, are different between the two populations, though well correlated (r = 0.83). In The Gambia, 80% of SNP pairs have the minor alleles in the repulsion phase, while in Malawi, 65% of SNP pairs are in the repulsion phase. Most of the SNP pairs in the repulsion phase have very low linkage disequilibrium (r2 = 0). There are six pairs of SNPs that are in the coupling phase in the Malawian sample, but are in the repulsion phase in The Gambian sample, reversing the allelic associations. Most of these occasions involve the TNF-244A allele, which is found on only one haplotype in the Gambia (in phase with the TNF-3025G allele), but on five different haplotypes in Malawi.

Bottom Line: We found 32 different haplotypes, of which 13 were shared between the two populations.We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure.The most informative subset of SNPs to genotype differs between the two populations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wellcome Trust for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. ackerman@fas.harvard.edu

ABSTRACT

Background: To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and population-based reconstruction methods.

Results: We found 32 different haplotypes, of which 13 were shared between the two populations. Both populations were haplotypically diverse (gene diversity = 0.80, Gambia; 0.85, Malawi) and significantly differentiated (p < 10-5 by exact test). More than a quarter of marker pairs showed evidence of intragenic recombination (29% Gambia; 27% Malawi). We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure. AEA revealed that many SNPs in TNF are poor markers of each other. The EMM showed that 8 of 12 SNPs (Gambia) and 7 of 12 SNPs (Malawi) are required to describe 95% of the haplotypic diversity.

Conclusions: The TNF locus in the Gambian and Malawi sample is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNF SNPs must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.

Show MeSH