Panning for gold: Genome-wide scanning for linkage in type 1 diabetes

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda(s) = 2.4). It is recognized that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T-lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells, However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda(s) = 1.25), cannot account for all of the observed clustering of disease in families (lambda(s) = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome, There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5(ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33). IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. Seven other named loci are not discounted but remain to be replicated widely, Multiple susceptibility loci were expected as genome-wide scans of the mouse model of type 1 diabetes had shown that although the MHC is the major mouse locus, at least 13 genes unlinked to the MHC are involved in the development of disease. Genome-wide scans using 1000 affected sibpair families will be required to be confident that all genes with effects on familial clustering equivalent to the insulin gene locus (lambda(s) = 1.25) have been detected. The identification of aetiological determinants requires exclusion of hitchhiking polymorphisms in regions of linkage disequilibrium, as demonstrated for the MHC and the insulin gene loci, and functional studies implicating the disease-associated variant in pathogenesis, Ultimately, targeting of specific candidate mutations in mice by homologous recombination and replacement will be necessary to prove the primary role of any candidate mutation.