Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study

Abstract

Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic hyperglycemia resulting from pancreatic beta-cell dysfunction and insulin resistance. Although the pathogenic mechanisms are not fully understood, manifestation of the disease most likely requires interaction between both environmental and genetic factors. In the search for such susceptibility genes, we have performed a genomewide scan in 58 multiplex families (comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland. Initially, linkage between chromosome 12q24 and impaired insulin secretion had been reported, by Mahtani et al., in a subsample of 26 families. In the present study, we extend the initial genomewide scan to include 32 additional families, update the affectation status, and fine map regions of interest, and we try to replicate the initial stratification analysis. In our analysis of all 58 families, we identified suggestive linkage to one region, chromosome 9p13-q21 (nonparametric linkage [NPL] score 3.9; P<.0002). Regions with nominal P values <.05 include chromosomes 2p11 (NPL score 2.0 [P<.03]), 3p24-p22 (NPL score 2.2 [P<.02]), 4q32-q33 (NPL score 2.5 [P<.01]), 12q24 (NPL score 2.1 [P<.03]), 16p12-11 (NPL score 1.7 [P<.05]), and 17p12-p11 (NPL score 1.9 [P<.03]). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal P value <.04 was observed. Together with data from other published genomewide scans, these findings lend support to the hypothesis that regions on chromosome 9p13-q21 and 12q24 may harbor susceptibility genes for type 2 diabetes.

Figure 1

Multipoint NPL analysis results for the NIDDM genomewide scan. Multipoint NPL scores were calculated by the GENEHUNTER version 2.0 software package (see the GENEHUNTER software-distribution web site). In each graph, the left vertical axis indicates the NPL score, represented by a thick line, the horizontal axis indicates the length of each chromosome, and the tick marks on the horizontal axis indicate the positions of the microsatellite markers; not all genotyped markers are represented. The shaded area indicates the recommended genomewide threshold (3.3 [Lander and Kruglyak 1995]) for suggestive linkage to a region.

Figure 2

Multipoint NPL score on chromosome 9, in the entire family, represented as described in the legend to figure 1 but in greater detail. The results for the initial 26 families are represented by a red line (D9S166 [NPL score 4.61 {P<.0001}]), the results for the additional 32 families are represented by a blue line (D9S166 [NPL score 1.09 {P=.14}]), and the combined results for all 58 families are represented by a black line (D9S166 [NPL score 3.9 {P<.0002}]). The shaded area indicates the recommended genomewide threshold (3.3 [Lander and Kruglyak 1995]) for suggestive linkage to a region.

Figure 3

Multipoint NPL score on chromosome 12 in two NIDDM genomewide scans, represented as described in the legend to figure 1. The results for the initial 26 families are represented by a red line (D12S304 [NPL score 1.2 {P<.2}]), the results for the additional 32 families are represented by a blue line (D12S366 [NPL score 1.8 {P<.04}]), the combined results for all 58 families are represented by a black line (D12S304–D12S1614 [NPL score 2.1 {P<.03}]), and the results of the new analysis of the 338 families described by Parker et al. (2001) are represented by a green line (D12S378 [NPL score 1.8 {P<.03}]).