A search for type 1 diabetes susceptibility genes in families from the United Kingdom

• DOI: 10.1038/991
• Publication Date: 2002-07-26T08:50:09Z
• Authors: CharlesA. Mein; Laura Esposito; Michael G. Dunn; Gillian C. L. Joh...; Andrew E. Timms; Juliet V. Goy; Annabel N. Smith; Liam Sebag-Montef...; Marilyn E. Merriman; Amanda J. Wilson; Lynn E. Pritchard; Francesco Cucca; Anthony H. Barnett; Stephen C. Bain; John A. Todd
• Keywords: Adult; 0303 health sciences; 03 medical and health sciences; Diabetes Mellitus, Type 1; Adolescent; Chromosome Mapping; Humans; Genetic Predisposition to Disease; United Kingdom; 3. Good health

Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (lambda(s)=2.5; refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at lambda(s)=3 and lod=-2, of which two showed evidence of linkage: chromosome 10p13-p11 (maximum lod score (MLS)=4.7, P=3x10(-6), lambda(s)=1.56) and chromosome 16q22-16q24 (MLS=3.4, P=6.5x10(-5), lambda(s)=1.6). These and other novel regions, including chromosome 14q12-q21 and chromosome 19p13-19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.