Perspective: the search for genes for type 2 diabetes in the post-genome era

Twin and family studies have demonstrated a strong genetic component to type 2 diabetes mellitus (T2DM), but mapping the susceptibility genes that account for this risk has proved difficult. At least seven single gene defects are known to cause T2DM, often with early onset and insulin deficiency, but these causes account for 5% or less of all T2DM. A large number of candidate genes have been evaluated for typical T2DM, but few have been confirmed in multiple studies, and among these, the effect on individual risk is modest. A large number of genome-wide scans have been published in the last few years, and at least four regions show evidence in multiple studies. However, only NIDDM1 has been mapped to a single gene, and that gene (calpain 10) appears to have a major role only in selected populations. Work is ongoing in many laboratories and multiple populations to map additional regions, but T2DM and other complex diseases have proved recalcitrant to current methodology. In addition to the ongoing progress in completing the genome sequence and in developing a comprehensive map of single nucleotide polymorphisms, new statistical models will be needed to incorporate the multiple loci with modest effect and the known environmental interactions that characterize the susceptibility to T2DM.