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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

Lookup NU author(s): Professor Mark Walker

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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 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 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.

Publication metadata

Author(s): Walker M; Wiltshire S; Hattersley AT; Hitman GA; Levy JC; Sampson M; O'Rahilly S; Frayling TM; Bell JI; Lathrop GM; Bennett A; Dhillon R; Fletcher C; Groves CJ; Jones E; Prestwich P; Simecek N; Rao PVS; Wishart M; Foxon R; Howell S; Smedley D; Cardon LR; Menzel S; McCarthy MI

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2001

Volume: 69

Issue: 3

Pages: 553-569

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1086/323249

DOI: 10.1086/323249

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