[PDF][PDF] Genomewide search for type 2 diabetes–susceptibility genes in French Whites: evidence for a novel susceptibility locus for early-onset diabetes on …

N Vionnet, S Dupont, S Gallina, S Francke… - The American Journal of …, 2000 - cell.com
N Vionnet, S Dupont, S Gallina, S Francke, S Dotte, F De Matos, E Durand, F Leprêtre
The American Journal of Human Genetics, 2000cell.com
Despite recent advances in the molecular genetics of type 2 diabetes, the majority of
susceptibility genes in humans remain to be identified. We therefore conducted a 10-cM
genomewide search (401 microsatellite markers) for type 2 diabetes–related traits in 637
members of 143 French pedigrees ascertained through multiple diabetic siblings, to map
such genes in the white population. Nonparametric two-point and multipoint linkage
analyzes—using the MAPMAKER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD …
Despite recent advances in the molecular genetics of type 2 diabetes, the majority of susceptibility genes in humans remain to be identified. We therefore conducted a 10-cM genomewide search (401 microsatellite markers) for type 2 diabetes–related traits in 637 members of 143 French pedigrees ascertained through multiple diabetic siblings, to map such genes in the white population. Nonparametric two-point and multipoint linkage analyzes—using the MAPMAKER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD (MLB) programs for autosomal markers and the ASPEX program for chromosome X markers—were performed with six diabetic phenotypes: diabetes and diabetes or glucose intolerance (GI), as well as with each of the two phenotypes associated with normal body weight (body-mass index<27 kg/m2) or early age at diagnosis (<45 years). In a second step, high-resolution genetic mapping (∼2 cM) was performed in regions on chromosomes 1 and 3 loci showing the strongest linkage to diabetic traits. We found evidence for linkage with diabetes or GI diagnosed at age <45 years in 92 affected sib pairs from 55 families at the D3S1580 locus on chromosome 3q27-qter using MAPMAKER-SIBS (MLS = 4.67, P=.000004), supported by the MLB statistic (MLB-LOD=3.43, P=.00003). We also found suggestive linkage between the lean diabetic status and markers APOA2D1S484 (MLS = 3.04, P=.00018; MLB-LOD=2.99, P=.00010) on chromosome 1q21-q24. Several other chromosomal regions showed indication of linkage with diabetic traits, including markers on chromosome 2p21-p16, 10q26, 20p, and 20q. These results (a) showed evidence for a novel susceptibility locus for type 2 diabetes in French whites on chromosome 3q27-qter and (b) confirmed the previously reported diabetes-susceptibility locus on chromosome 1q21-q24. Saturation on both chromosomes narrowed the regions of interest down to an interval of <7 cM.
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