Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6) |
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Authors: | Merriman TR; Eaves IA; Twells RC; Merriman ME; Danoy PA; Muxworthy CE; Hunter KM; Cox RD; Cucca F; McKinney PA; Shield JP; Baum JD; Tuomilehto J; Tuomilehto- Wolf E; Ionesco-Tirgoviste C; Joner G; Thorsby E; Undlien DE; Pociot F; Nerup J; Ronningen KS; Bain SC; Todd JA |
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Institution: | The Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, Windmill Road, Headington, Oxford OX3 7BN, UK. |
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Abstract: | Allelic association methods based on increased transmission of marker
alleles will have to be employed for the mapping of complex disease
susceptibility genes. However, because the extent of association of single
marker alleles with disease is a function of the relative frequency of the
allele on disease-associated chromosomes versus non disease-predisposing
chromosomes, the most associated marker allele in a region will not
necessarily be closest to the disease locus. To overcome this problem we
describe a haplotype-based approach developed for mapping of the putative
type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers
spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region
were genotyped in 1708 type 1 diabetic Caucasian families from seven
countries. The most likely ancestral diabetogenic chromosome was
reconstructed in a stepwise fashion by analysing linkage disequilibrium
between a previously defined haplotype of three adjacent markers and the
next marker along the chromosome. A plot of transmission from heterozygous
parents to affected offspring of single marker alleles present on the
ancestral chromosome versus the physical distance between them, was
compared with a plot of transmission of haplotypes of groups of three
adjacent markers. Analysing transmission of haplotypes largely negated
apparent decreases in transmission of single marker alleles. Peak support
for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P
= 0.01). The results also demonstrate the utility of polymorphic
microsatellite markers to trace and delineate extended and presumably
ancient haplotypes in the analysis of common disease and in the search for
identical-by-descent chromosome regions that carry an aetiological variant.
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