Nature Genetics
19, 297 - 300 (1998)
doi:10.1038/991
A search for type 1 diabetes susceptibility genes in families from the
United KingdomCharlesA. Mein1, Laura Esposito1, Michael G. Dunn1, Gillian C. L. Johnson1, Andrew E. Timms1, Juliet V. Goy1, Annabel N. Smith1, Liam Sebag-Montefiore1, Marilyn E. Merriman1, Amanda J. Wilson1, Lynn E. Pritchard1, Francesco Cucca1, Anthony H. Barnett2, Stephen C. Bain2
& John A. Todd11
Wellcome Trust Centre for Human Genetics, Nuffield
Department of Surgery, University of Oxford, Windmill Road,
Oxford OX3 7BN, UK. 2
Department of Medicine, University of Birmingham, Birmingham
Heartlands Hospital, Birmingham B9 5SS, UK.
Correspondence should be addressed to John A. Todd 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 ( 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 s
= 3 and lod = −2, of which two showed evidence of linkage: chromosome
10p13−p11 (maximum lod score (MLS) = 4.7, P = 3  10
−6, s = 1.56) and chromosome 16q22−16q24
(MLS = 3.4, P = 6.5 10−5,
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-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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