Bridging the gap between genetic associations and molecular mechanisms for type 2 diabetes

Type 2 diabetes is a global pandemic for which there is currently no disease-modifying treatment. New and targeted therapeutics are greatly needed, but progress in identifying novel targets for therapeutic intervention is severely hampered by poor understanding of disease pathogenesis. Over the past 6 years, the success of genome-wide association studies has led to an unprecedented increase in the number of loci robustly associating with type 2 diabetes risk. Each of these signals offers the opportunity to uncover biological insights into disease pathogenesis, which, if harnessed effectively, hold the promise to deliver new pathways for therapeutic intervention, strategies for patient stratification, and potentially, biomarkers for identifying those at greatest risk of developing diabetes. We review the progress that has been made and the approaches being adopted and discuss the inherent challenges in moving from association signals, which largely map to poorly annotated sequence, to transcripts, mechanisms, and disease biology.