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

Steven Wiltshire, Andrew T. Hattersley, Graham A. Hitman, Mark Walker, Jonathan C. Levy, Michael Sampson, Stephen O’rahilly, Timothy M. Frayling, John I. Bell, G. Mark Lathrop, Amanda Bennett, Ranjit Dhillon, Christopher Fletcher, Christopher J. Groves, Elizabeth Jones, Philip Prestwich, Nikol Simecek, Pamidighantam V. Subba Rao, Marie Wishart, Richard FoxonSimon Howell, Damian Smedley, Lon R. Cardon, Stephan Menzel, Mark I. McCarthy

Research output: Contribution to journalArticlepeer-review

271 Scopus citations

Abstract

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores ≥1.18 (P ≤. 01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, 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 1q24-25 (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. After 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 revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P =. 01) and 5q32 (P =. 02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

Original languageEnglish
Pages (from-to)553-569
Number of pages17
JournalAmerican Journal of Human Genetics
Volume69
Issue number3
DOIs
StatePublished - Sep 2001
Externally publishedYes

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