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 nearly 10,000 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. Currently we are focused on fine mapping of regions on chromosomes 6, 11, 14, 20, and 22 where linkage analyses have shown evidence for susceptibility genes for diabetes or related traits. 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 P2 promoter of the HNF4A transcription factor. These variants seem to account for much of the linkage signal, and have now been confirmed by several other groups. We are in the process of carrying out fine mapping of linkage signals on chromosomes 6, 11, and 14, using the HapMap data to optimize the choice of markers. We have also tested a number of attractive candidate genes in our large sample, and identified several that show strong evidence of association with T2D. Finally, 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. With this kind of substantial progress, we are confident that the """"""""geneticist's nightmare"""""""" (Jim Neel's description of the genetics of diabetes) may be coming to an end.
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