Mein, Charles A. and Esposito, Laura and Dunn, Michael G. and Johnson, Gillian C. L. and Timms, Andrew E. and Goy, Juliet V. and Smith, Annabel N. and Sebag Montefiore, Liam M. and Merriman, Marilyn E. and Wilson, Amanda J. and Pritchard, Lynn E. and Cucca, Francesco and Barnett, Anthony H. and Bain, Stephen Charles and Todd, John A. (1998) A Search for type 1 diabetes susceptibility genes in families from the United Kingdom. Nature Genetics, Vol. 19 (3), p. 297-300. eISSN 1546-1718. Article.
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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 (λs=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 λs=3 and lod=-2, of which two showed evidence of linkage: chromosome 10p13-p11 (maximum lod score (MLS)=4.7, P=3x10-6, λs=1.56) and chromosome 16q22-16q24 (MLS=3.4, P=6.5x10-5, λs)= 1.6). These and other novel regions, including chromosome 14q12-q21 and chromosome 19p1319q13, 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.
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