A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians

Abstract

The prevalence of type 2 diabetes among Australian residents is 7.5%; however, prevalence rates up to six times higher have been reported for indigenous Australian communities. Epidemiological evidence implicates genetic factors in the susceptibility of indigenous Australians to type 2 diabetes and supports the hypothesis of the "thrifty genotype," but, to date, the nature of the genetic predisposition is unknown. We have ascertained clinical details from a community of indigenous Australian descent in North Stradbroke Island, Queensland. In this population, the phenotype is characterized by severe insulin resistance. We have conducted a genomewide scan, at an average resolution of 10 cM, for type 2 diabetes-susceptibility genes in a large multigeneration pedigree from this community. Parametric linkage analysis undertaken using FASTLINK version 4.1p yielded a maximum two-point LOD score of +2.97 at marker D2S2345. Multipoint analysis yielded a peak LOD score of +3.9 <1 cM from marker D2S2345, with an 18-cM 3-LOD support interval. Secondary peak LOD scores were noted on chromosome 3 (+1.8 at recombination fraction [theta] 0.05, at marker D3S1311) and chromosome 8 (+1.77 at theta=0.0, at marker D8S549). These chromosomal regions are likely to harbor novel susceptibility genes for type 2 diabetes in the indigenous Australian population.

Figure 1

Pedigree structure. Blackened symbols denote individuals with type II diabetes. Unblackened symbols denote unaffected individuals. The arrow indicates the proband.

Figure 2

Graphs of two-point LOD scores at θ=0.01, for each autosome from the genomewide scan. The x-axes represent distance in centimorgans, and the y-axes represent two-point LOD scores.

Figure 3

Graph of multipoint LOD scores for chromosome 2q. Marker positions are sex-averaged and are calculated on the basis of The Genetic Location Database.