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

Tony Merriman, Rebecca Twells, Marilyn Merriman, Lain Eaves, Roger Cox, Francesco Cucca, Patricia McKinney, Julian Shield, David Baum, Emanuele Bosi, Paolo Pozzilli, Lorenza Nisticò, Raffaella Buzzetti, Geir Joner, Kjersti Rønningen, Erik Thorsby, Dag Undlien, Flemming Pociot, Jørn Nerup, Stephen BainAnthony Barnett, John Todd

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1003-1010
Number of pages8
JournalHuman Molecular Genetics
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 1997

ASJC Scopus subject areas

  • Genetics

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