A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed <jats:italic>Drosophila</jats:italic> model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Disrupting orthologs of certain T2D candidate genes (<jats:italic>HHEX</jats:italic>, <jats:italic>THADA</jats:italic>, <jats:italic>PPARG</jats:italic>, <jats:italic>KCNJ11</jats:italic>) led to sucrose-dependent toxicity. Tissue-specific knockdown of the <jats:italic>HHEX</jats:italic> ortholog <jats:italic>dHHEX</jats:italic> (<jats:italic>CG7056</jats:italic>) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of <jats:italic>dHHEX</jats:italic> led to increased hemolymph glucose and reduced insulin sensitivity.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple <jats:italic>Drosophila</jats:italic> approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.</jats:p> </jats:sec>