A genomewide scan for type 1-diabetes susceptibility in Scandinavian families: Identification of new loci with evidence of interactions

Type 1 diabetes mellitus (TIDM) has a multifactorial etiology, with major g enetic-susceptibility determinants located in the HLA and insulin-gene (INS ) regions. Linkage data implicating other disease-susceptibility loci are c onflicting. This is likely due to (1) the limited power for detection of co ntributions of additional susceptibility loci, given the limited number of informative families available for study, (2) factors such as genetic heter ogeneity between populations, and (3) potential gene-gene and gene-environm ent interactions. To circumvent some of these problems, we have conducted a genomewide linkage analysis for T1DM-susceptibility loci in 408 multiplex families from Scandinavia, a population expected to be homogeneous for gene tic and environmental factors. In addition to verifying the HLA and INS sus ceptibility loci, the study provides confirmation of IDDM15 on chromosome 6 q21. Suggestive evidence of additional susceptibility loci was found on chr omosomes 2p, 5q, and 16p. For some loci, the support for linkage increased substantially when families were stratified on the basis of HLA or INS geno types, with statistically significant heterogeneity between the stratified subgroups. Our data support both the existence of non-HLA genes of signific ance for T1DM and interaction between HLA and non-HLA loci in the determina tion of the T1DM phenotype.