Type 2 diabetes and obesity: genomics and the clinic

Abstract

Type 2 diabetes (T2D) and obesity represent major challenges for global public health. They are at the forefront of international efforts to identify the genetic variation contributing to complex disease susceptibility, and recent years have seen considerable success in identifying common risk-variants. Given the clinical impact of molecular diagnostics in rarer monogenic forms of these diseases, expectations have been high that genetic discoveries will transform the prospects for risk stratification, development of novel therapeutics and personalised medicine. However, so far, clinical translation has been limited. Difficulties in defining the alleles and transcripts mediating association effects have frustrated efforts to gain early biological insights, whilst the fact that variants identified account for only a modest proportion of observed familiarity has limited their value in guiding treatment of individual patients. Ongoing efforts to track causal variants through fine-mapping and to illuminate the biological mechanisms through which they act, as well as sequence-based discovery of lower-frequency alleles (of potentially larger effect), should provide welcome acceleration in the capacity for clinical translation. This review will summarise recent advances in identifying risk alleles for T2D and obesity, and existing contributions to understanding disease pathology. It will consider the progress made in translating genetic knowledge into clinical utility, the challenges remaining, and the realistic potential for further progress.