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

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(1,2) 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 stilt 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 = 3 x 10(-6), lambda(s) = 1.56) and chromosome 16q22-16q24 (MLS = 3.4, P = 6.5 x 10(-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(5-7) and haplotype mapping approaches(8) must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage(6,8-13).