Genetic analysis of type II diabetes in Finnish populati

Human Genome Research

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Abstract

Type 2 diabetes (T2D) is one of the major causes of morbidity and mortality in the developed world. While environmental factors such as diet play a significant role, familial clustering indicates that there must be significant genetic suscepibility factors at work. For ten years we have been engaged in a large collaborative study entitled FUSION (Finland - United States Investigation of NIDDM), in which over 5000 individuals with diabetes (and suitable controls) from Finland are being studied, using careful phenotyping of diabetes and diabetes associated traits, and genome-wide genetic linkage and association. We have developed new approaches in the laboratory to achieve high throughput microsatellite and SNP genotyping, which has allowed the collection of a massive amount of data from these Finnish diabetics and their families. During FY 2002 this project has made significant progress, focusing on fine mapping of regions on chromosomes 6, 11, 14, 20, and 22 where prior linkage analyses have shown evidence for susceptibility genes for diabetes or related traits. In particular, we have identified a small region on chromosome 22 which contains a haplotype conferring an odds ratio of 1.5 for T2D, and which has been confirmed and narrowed by studying a West African diabetic population. On the long arm of chromosome 20, a region where a dozen groups have independently shown evidence of linkage for T2D, we have identified susceptibility variants in a small region of the promoter of an excellent candidate gene. These variants seem to account for most or all of the linkage signal, and have just been confirmed in an independent study of Ashkenazi diabetics. We have also identified an attractive candidate gene on chromosome 11 that carries a P-value <0.001 for T2D association. With this kind of substantial progress, and the emerging haplotype map of the human genome to guide additional SNP selection, we are confident that the "geneticist's nightmare" (Jim Neel's description of the genetics of diabetes) may be coming to an end.