Type 1 diabetes - Evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families

Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [lambda] similar to 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific lambda(S) similar to 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allefic odds ratio [OR] similar to 1.9), CTLA4 (chromosome 2q33, allelic OR similar to 1.2), and PTPN22 (chromosome. 1p13, allelic OR similar to 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In Addition to the H LA region (nominal P = 2.0 x 10(-52)), nine non-HLA-linked regions showed evidence of linkage to type 1 diabetes (nominal P < 0.01), including, three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10(-4)). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect (lambda(S) >= 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, l0p14-q11, and 16q22-q24 but diminished support for some previously reported locations.