Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2

Abstract

We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 2.90, P=1.29 x 10(-4)) in all diabetics. Since obesity, here defined as body mass index (BMI) > or =30 kg/m(2), is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI > or =30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 3.64, P=2.12 x (10)-5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12 x 10(-5)) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.

Figure 1

Genomewide scan using 906 microsatellite markers. Results are shown for three phenotypes: all type 2 diabetics (black lines), obese diabetics (red lines), and nonobese diabetics (blue lines). The multipoint LOD score is on the vertical axis, and the centiMorgan distance from the p-terminus of the chromosome is on the horizontal axis.

Figure 2

Multipoint allele-sharing LOD score of a portion of chromosome 5 after 38 microsatellite markers have been added to the framework marker set in a 40-cM interval from 160 cM to 200 cM. The average distance between the markers in the peak reagion is 0.84 cM. Results are shown for the same three phenotypes as in figure 1, and the location of the markers is indicated with green vertical bars at the top of the figure.

Figure 3

a, Positive interaction between the loci on chromosomes 5 and 12. Multipoint allele-sharing LOD score of a portion of chromosome 12 after 21 microsatellite markers have been added to the framework marker set. Results are shown for all nonobese diabetics (black line) and for nonobese diabetics in positive-NPL families on chromosome 5 (red line). b, Negative interaction between the loci on chromosomes 5 and 10. Multipoint allele-sharing LOD score of a portion of chromosome 10 after 8 microsatellite markers have been added to the framework marker set. Results are shown for all nonobese diabetics (black line) and for nonobese diabetics in negative-NPL families on chromosome 5 (blue line).

Figure 4

The effects of imprinting on the LOD score on chromosome 5. Maternal versus paternal effect on chromosome 5 locus. Results are shown for all nonobese diabetics (black line), nonobese diabetics with maternal inheritance (red line), and nonobese diabetics with paternal inheritance (blue line).