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Haplotype tagging for the identification of common disease genes

Abstract

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated1,2,3, even the most recent studies2,4 have not placed significant emphasis on the most informative and cost-effective method of LD mapping—that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

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Figure 1: Relationship between |D′|, d2 and physical distance.
Figure 2: Polymorphisms detected and genotyped at CTLA4.
Figure 3: Common European haplotypes and their htSNPs observed at nine genes.
Figure 4: Relationship between allele/haplotype frequency and sample-size requirements for population-based association studies.

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Acknowledgements

We are grateful to L. Smink for advice. This work was funded by the Wellcome Trust, the Juvenile Diabetes Research Foundation International, Diabetes UK and grants from the Finnish Academy (38387, 46558, 52114, and 51225), Novo Nordisk Foundation and Sigrid Juselius Foundation. G.C.L.J. was the recipient of a Diabetes UK PhD Studentship.

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Correspondence to John A. Todd.

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Johnson, G., Esposito, L., Barratt, B. et al. Haplotype tagging for the identification of common disease genes. Nat Genet 29, 233–237 (2001). https://doi.org/10.1038/ng1001-233

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