TRANSMISSION OF HAPLOTYPES OF MICROSATELLITE MARKERS RATHER THAN SINGLE MARKER ALLELES IN THE MAPPING OF A PUTATIVE TYPE-1 DIABETES SUSCEPTIBILITY GENE (IDDM6)

Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease su sceptibility genes. However, because the extent of association of sing le marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-pr edisposing 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 microsa tellite markers spanning a 550 kb segment of chromosome 18q21 in the p utative 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 linkag e disequilibrium between a previously defined haplotype of three adjac ent markers and the next marker along the chromosome. A plot of transm ission from heterozygous parents to affected offspring of single marke r alleles present on the ancestral chromosome versus the physical dist ance between them, was compared with a plot of transmission of haploty pes of groups of three adjacent markers. Analysing transmission of hap lotypes largely negated apparent decreases in transmission of single m arker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrat e the utility of polymorphic microsatellite markers to trace and delin eate extended and presumably ancient haplotypes in the analysis of com mon disease and in the search for identical-by-descent chromosome regi ons that carry an aetiological variant.