Translating genetic association signals for diabetes and metabolic traits into molecular mechanisms for disease

© 2014 S. Karger AG, Basel. More than 80 genetic loci affecting type 2 diabetes (T2D) risk have been published to date. However, the causative variant(s) and biology underlying the associations at the vast majority of these loci remain elusive, in part due to an incomplete understanding of the genes and pathways involved in T2D development and progression. This highlights two interrelated challenges: the need for functional elucidation of the effects of individual variants, and the need to broadly and comprehensively investigate the function of implicated genes to understand how their modulation contributes to disease risk. This chapter discusses the approaches beginning to bear fruit in addressing both of these challenges, including the characterization of nonsynonymous common variants or collections of rare variants (e.g. GCKR , MTNR1B ), the assignment of novel gene function relevant to disease processes (e.g. CDKAL1 ), the value of integrating genetic association results with datasets for expression or epigenetic factors (e.g. TCF7L2 , KLF14 ), and emerging systems genetics approaches focusing on pathways, protein-protein interactions, and gene-gene interactions. These instructive studies suggest a template for future functional investigations into the variants and genes underlying T2D risk.