title: 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 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Mein
authors.forename: L
authors.initials: L
authors.lastname: Esposito
authors.forename: M G
authors.initials: MG
authors.lastname: Dunn
authors.forename: G C
authors.initials: GC
authors.lastname: Johnson
authors.forename: A E
authors.initials: AE
authors.lastname: Timms
authors.forename: J V
authors.initials: JV
authors.lastname: Goy
authors.forename: A N
authors.initials: AN
authors.lastname: Smith
authors.forename: L
authors.initials: L
authors.lastname: Sebag-Montefiore
authors.forename: M E
authors.initials: ME
authors.lastname: Merriman
authors.forename: A J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: L E
authors.initials: LE
authors.lastname: Pritchard
authors.forename: F
authors.initials: F
authors.lastname: Cucca
authors.forename: A H
authors.initials: AH
authors.lastname: Barnett
authors.forename: S C
authors.initials: SC
authors.lastname: Bain
authors.forename: J A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000293:Adolescent; D000328:Adult; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006113:United Kingdom