Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21

Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes byaffected sibpair linkage analysis is not practical and allelic associationor linkage disequilibrium mapping will have to be employed to attempt todetect founder chromosomes. Given prior evidence of linkage of theJk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluatedthe 12 informative microsatellite markers in the region for linkage withdisease by the transmission disequilibrium test (TDT) in a UK data set oftype 1 diabetic families (n = 195). Increased transmission of allele 4 ofmarker D18S487 to affected children was detected (P = 0.02). Support forthis was extended in a total of 1067 families from four different countriesby isolating, and evaluating by the TDT, two novel microsatellites within70 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 increasedtransmission of associated alleles to nonaffected siblings. Analysis of anadditional 390 families by the TDT did not extend the evidence further, andreduced support in the total 1457 families to P = 0.001 for linkage and P =0.003 for association. However, evidence for linkage by affected sibpairallele 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 forby the presence of more than one common disease- associated haplotype(allelic heterogeneity) which confounds the analysis of individual allelesby the TDT. Guidelines for strategies for the mapping of polygenes aresuggested with the emphasis on collections of large numbers of familiesfrom multiple populations that should be as genetically homogeneous aspossible.