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

Abstract

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 genome1,2. 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 (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 = 3 × 10–6, λs = 1.56) and chromosome 16q22–16q24 (MLS = 3.4, P = 6.5 × 10–5, λs = 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-based5,6,7 and haplotype mapping approaches8 must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage6,8,9,10,11,12,13.

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Figure 1: Multipoint linkage analysis of chromosome 16.

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Acknowledgements

This work was funded by the Wellcome Trust, British Diabetic Association, UK Medical Research Council, Juvenile Diabetes Foundation International, Merck Research Laboratories and Lilly Industries, UK. L.E. was supported by an E.C. Biomedicine and Health Fellowship. J.A.T. is a Wellcome Trust Principal Research Fellow. We thank M. Murphy, S. Howell, C. Smyth, J. Carr-Smith, the British Diabetic Association and the Human Biological Data Interchange for family collection.

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Mein, C., Esposito, L., Dunn, M. et al. A search for type 1 diabetes susceptibility genes in families from the United Kingdom. Nat Genet 19, 297–300 (1998). https://doi.org/10.1038/991

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