INVESTIGATION OF LINKAGE OF CHROMOSOME-8 TO TYPE-1 DIABETES - MULTIPOINT ANALYSIS AND EXCLUSION MAPPING OF HUMAN-CHROMOSOME-8 IN 593 AFFECTED SIB-PAIR FAMILIES FROM THE UK AND US

Type 1 diabetes is a common multifactorial disease that is strongly cl ustered in families: the sibling risk-to-population prevalence ratio ( lambda(s)) is 15 (6%/0.4%) (1). Two loci, IDDM1 in the major histocomp atibility complex (MHC) on chromosome 6p21 and IDDM2 in the insulin ge ne (INS) region of chromosome 11p15.5 can account for similar to 50% o f the observed familial clustering (1). Locus-specific lambda(s) value s (1) in 356 U.K. affected sib-pair families (2) for IDDM1 and IDDM2 a re 3.0 and 1.3, respectively, or 41 and 8%, assuming a multiplicative model (J.A.T., unpublished observations). The rapid reduction in risk from first- to second- to third-degree relatives of type 1 diabetic pa tients (3) and whole genome scanning of a spontaneous mouse model of a utoimmune type 1 diabetes (4,5) suggest that other genes may account f or the rest of the familial clustering (1,4,5). In humans, two genome- wide scans, both based on the analysis of affected sib pairs, have bee n published so far (6,7), with the larger scan evaluating 290 markers in 96 U.K. families (data were analyzed in 93 of these families, so he nceforth, this scan will be referred to as the 93 U.K. family scan) (6 ). The main conclusions of these studies were that the presence elsewh ere in the genome of a second gene with an effect similar to IDDM1 (la mbda(s) = 3) is unlikely, and that other genes with lambda(s) < 3 are involved. Subsequently, additional evidence for linkage to some of the se and other regions has been reported (8-10).