Haplotypic analysis of the TNF locus by association efficiency and entropy.
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.
Ackerman
Hans
H
Wellcome Trust for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. ackerman@fas.harvard.edu
Usen
Stanley
S
Mott
Richard
R
Richardson
Anna
A
Sisay-Joof
Fatoumatta
F
Katundu
Pauline
P
Taylor
Terrie
T
Ward
Ryk
R
Molyneux
Malcolm
M
Pinder
Margaret
M
Kwiatkowski
Dominic P
DP
D000328:Adult; D016022:Case-Control Studies; D019277:Entropy; D005714:Gambia; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008295:Malawi; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha