A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians

Considerable evidence supports a major inherited component of type 2 diabet es. We initially conducted a genome-wide scan with 440 microsatellite marke rs at 10-cM intervals in 19 multigenerational families of Northern European ancestry with at least two diabetic siblings. Initial two-point analyses o f these families directed marker typing of 23 additional families. Subseque ntly, all available marker data on the total of 42 families were analyzed u sing both parametric and nonparametric multipoint methods to test for linka ge to type 2 diabetes. One locus on chromosome 1q21-1q23 met genome-wide cr iteria for significant Linkage under a model of recessive inheritance with a common diabetes allele (logarithm of odds [LOD] = 4.295), Both pedigree-b ased nonparametric Linkage (NPL) analysis and affected sib pair (MAPMAKER/S IBS) nonparametric methods also showed the highest genome-wide scores at th is region, near markers CRP and APOA2, but failed to meet levels of genome- wide significance. The risk of type 2 diabetes to siblings of a diabetic pe rson when compared with the population (lambda(s)) was estimated from MAPMA KER/SIBS to be 2.8 in these 42 families. Simulation studies using study dat a confirmed a genome-wide significance level of P < 0.05 (95% CI 0.005-0.04 66), However, analysis of 20 similarly ascertained but smaller families fai led to confirm this linkage. The LOD score with 50% heterogeneity for all 6 2 families considered together was only 2.25, with an estimated gamma(s) of 1.87, Our data suggest a novel diabetes susceptibility locus near APOA2 on chromosome 1 in a region with many transcribed genes.