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 susceptibility factors at work. For sixteen years we have been engaged in a large collaborative study entitled FUSION (Finland - United States Investigation of NIDDM), in which more than 10,000 individuals with diabetes (and suitable controls) from Finland are being studied, using careful phenotyping of diabetes and diabetes-associated quantitative traits, and genome-wide genetic linkage and association. Large numbers of additional samples are also now available from several collaborators around the world. We have developed and applied new high throughput genotyping approaches in the laboratory, which have allowed the collection of a massive amount of data from these Finnish diabetics and their families. Using the genome wide association study (GWAS) approach, we have now contributed to the identification of no less than 38 loci for T2D, and have identified additional loci harboring variants that have important effects on obesity, fasting glucose, LDL and HDL cholesterol, triglycerides, blood pressure, and adult height. We are now investigating the functional basis of disease risk that arises from several of these variants, including those in WFS, TCF7L2, SLC30A8, IGF2BP2, HMGCR and GCKR. This analysis includes high throughput sequencing of these loci to identify common and rare alleles that may be driving the association, analysis of the relationship between gene expression, and risk haplotypes, and cell culture and biochemical assays. A major effort has been devoted to defining the epigenome of the human pancreatic islet, by mapping a variety of chromatin marks across the entire genome. This has enabled identification of enhancers and insulators, some of which harbor variants that influence the risk of T2d. With this kind of substantial progress, we are confident that the geneticist's nightmare (Jim Neel's description of the genetics of diabetes) is coming to an end.
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