Target gene discovery in extended families with type 2 diabetes mellitus

Type 2 diabetes mellitus is a polygenic, multifactorial disease. Multiple attempts have been made to identify genes that predispose to development of diabetes using both the candidate gene approach and whole genome scanning. However, in spite of substantial financial commitment, very few targets have been identified. Identification of predisposing genes is complicated by several factors. Diabetic patients demonstrate a variety of gene defect combinations. Identification of predisposing genomic regions is thus impeded if data are collected from a heterogeneous population. In addition, the diseased phenotype may only manifest when the net effect of the predisposing factors exceeds a certain 'threshold'. The effects of predisposing genetic and environmental factors thus appear to be additive, and this also complicates target gene discovery. Using the traditional approach, significant associations between genomic regions and disease are rarely observed unless data are acquired from hundreds of individuals. In contrast, results from whole genome scans performed in homogeneous and consanguineous populations with a high incidence of type 2 diabetes have demonstrated that highly significant associations can be obtained using data from a small number of subjects belonging to the same extended family. Such populations offer the promise of substantial progress in type 2 diabetes genomics research.