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Abstract
BackgroundGenome-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 Drosophila 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.ResultsDisrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.ConclusionCandidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila 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.
Highlights
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
We show in one region that HHEX may contribute to type 2 diabetes phenotypes including hyperglycemia and insulin insensitivity; in addition, our data suggests two neighboring genes may contribute to the risk identified by GWAS
Human GWAS traits, associated index Single nucleotide polymorphism (SNP), genomic regions, candidate genes, and fly orthologs are listed in Table 1 and Additional file 1: Table S1
Summary
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. Genome-wide association studies (GWAS) have had success in identifying susceptibility loci for type 2 diabetes and related traits in humans [4,5]. These studies establish associations between markers, such as single nucleotide polymorphisms (SNPs), and disease. They typically lack the resolution needed to identify causal variants, because SNPs may exist in linkage disequilibrium with multiple protein-coding loci as well as with non-coding gene-regulatory elements that can act over a long distance [6,7]. Drosophila melanogaster raised on diets high in sugar exhibit hallmark features of type 2 diabetes including insulin resistance, fasting hyperglycemia, and increased fat storage [10]
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