Human Molecular Genetics, Vol 6, 1003-1010, Copyright © 1997 by Oxford University Press
T Merriman, R Twells, M Merriman, I Eaves, R Cox, F Cucca, P McKinney, J Shield, D Baum, E Bosi, P Pozzilli, L Nistico, R Buzzetti, G Joner, K Ronningen, E Thorsby, D Undlien, F Pociot, J Nerup, S Bain, A Barnett and J Todd
Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes by
affected sibpair linkage analysis is not practical and allelic association
or linkage disequilibrium mapping will have to be employed to attempt to
detect founder chromosomes. Given prior evidence of linkage of the
Jk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluated
the 12 informative microsatellite markers in the region for linkage with
disease by the transmission disequilibrium test (TDT) in a UK data set of
type 1 diabetic families (n = 195). Increased transmission of allele 4 of
marker D18S487 to affected children was detected (P = 0.02). Support for
this was extended in a total of 1067 families from four different countries
by isolating, and evaluating by the TDT, two novel microsatellites within
70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5)
and 3 x 10(-4), respectively. There was no evidence for increased
transmission of associated alleles to nonaffected siblings. Analysis of an
additional 390 families by the TDT did not extend the evidence further, and
reduced support in the total 1457 families to P = 0.001 for linkage and P =
0.003 for association. However, evidence for linkage by affected sibpair
allele sharing was strong (P = 3.2 x 10(-5)) in the second data set.
Heterogeneity in TDT results between data sets was, in part, accounted for
by the presence of more than one common disease- associated haplotype
(allelic heterogeneity) which confounds the analysis of individual alleles
by the TDT. Guidelines for strategies for the mapping of polygenes are
suggested with the emphasis on collections of large numbers of families
from multiple populations that should be as genetically homogeneous as
possible.
ARTICLES
Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21
The Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, UK.
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