SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES-MELLITUS MAPS TO A LOCUS(IDDM11) ON HUMAN-CHROMOSOME 14Q24.3-Q31

To locate genes predisposing to insulin-dependent diabetes mellitus (I DDM), an autoimmune disorder resulting from destruction of the insulin -producing pancreatic cells, we are testing linkage of IDDM susceptibi lity to polymorphic markers across the genome using families with two or more IDDM children. A new susceptibility locus (IDDM11) has been lo calized to chromosome 14q24.3-q31 by detection of significant linkage to microsatellite D14S67, using both maximum likelihood methods (LOD(m ax) = 4.0 at theta = 0.20) and affected sib pair (ASP) methods (P = 1 x 10(-5)). This represents the strongest reported evidence for linkage to any IDDM locus outside the HLA region. The subset of families in w hich affected children did not show increased sharing of HLA genes (HL A sharing less than or equal to 50%) provided most of the support for D14S67 linkage (LOD(max) 4.6 at theta = 0.12; ASP P < 5 x 10(-6)). The re was significant linkage heterogeneity between the HLA-defined subse ts of families (P = 0.009), suggesting that IDDM11 may be an important susceptibility locus in families lacking strong HLA region predisposi tion. (C) 1996 Academic Press, Inc.