Seven regions of the genome show evidence of linkage to type 1 diabetes ina consensus analysis of 767 multiplex families

Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeosta sis that results from the autoimmune destruction of the insulin-secreting c ells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparent ly conflicting results, despite partial overlap in the families analyzed. H owever, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda (s))<1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these geno me scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with <lambda>(s) p 1.3 at P=7.4 x 10(-4). Three chromosome regions wer e identified that showed significant evidence of linkage (P<2.2 x 10(-5); L OD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22- q24, and four more that showed suggestive evidence (P<7.4 x 10(-4), LOD scores <greater than or equ al to>2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15) , and 1q42. Exploratory analyses, taking into account the presence of speci fic high-risk HLA genotypes or affected sibs' ages at disease onset, provid ed evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the diffi culty in mapping T1D susceptibility genes results from inadequate sample si zes, and the results point to the value of future international collaborati ons to assemble and analyze much larger data sets for linkage in complex di seases.