A genomewide scan for loci predisposing to type 2 diabetes in a UK population (the Diabetes UK Warren 2 repository): Analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extende d. To identify diabetes-susceptibility genes, we have completed a primary ( 418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) wi th type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonpar ametric linkage analysis of the entire data set identified seven regions sh owing evidence for linkage, with allele-sharing LOD scores greater than or equal to1.18 (P less than or equal to .01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D1 0S1765 [LOD score 1.99]), both coinciding with regions identified in previo us scans in European subjects. This was also true of two lesser regions ide ntified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q2 4-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. Aft er dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revea led nominally significant interactions between this locus and the regions o n chromosomes 10q23.3 (P = .01) and 5q32 ( P = .02). These data, derived fr om one of the largest genome scans undertaken in this condition, confirm th at individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they prov ide both replication of previous evidence indicating the presence of a diab etes-susceptibility locus on chromosome 1q24-25 and support for the existen ce of additional loci on chromosomes 5, 8, and 10. These data should accele rate positional cloning efforts in these regions of interest.