PANNING FOR GOLD - GENOMEWIDE SCANNING IN TYPE-1 DIABETES (REPRINTED FROM HUMAN MOLECULAR-GENETICS, VOL 5, PG 1443-1448, 1996)

Genomewide scans for linkage of chromosome regions to type 1 diabetes in affected-sib pair families have revealed that the major susceptibil ity locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda(s) = 2.4). However, the MHC genes and a secon d locus, he insulin gene minisatellite an chromosome 11p15 (IDDM2; lam bda(s) = 1.25), cannot account for all of the observed clustering of d isease in families (lambda(s) = 15), and the scans suggested the prese nce of other susceptibility loci scattered throughout the genome. Ther e are four additional loci for which there is currently sufficient evi dence from linkage and association studies to justify fine mapping exp eriments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27), a nd IDDM12 (CTLA-4/2q33). IDDM4, IDDM5, and IDDM8 were detected by geno me scanning and IDDM12 by a candidate-gene strategy. Genomewide scans using 1,000 affected-sib pair families will be required if we are to b e confident that all genes with effects on familial clustering equival ent to the insulin gene locus (lambda(s) = 1.25) have been detected. T he identification of etiologic determinants requires exclusion of hitc hhiking polymorphisms lan regions of linkage disequilibrium, as demons trated for the MHC and the insulin gene loci, and functional studies i mplicating the disease-associated variant in pathogenesis. Ultimately, targeting of specific candidate mutations iia mice by homologous reco mbination and replacement will be necessary to prove the primary role of any candidate mutation.