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Open Access Research article

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

Jay Pendse1, Prasanna V Ramachandran2, Jianbo Na1, Narisu Narisu3, Jill L Fink2, Ross L Cagan1, Francis S Collins3 and Thomas J Baranski2*

Author affiliations

1 Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA

2 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

3 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

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Citation and License

BMC Genomics 2013, 14:136  doi:10.1186/1471-2164-14-136

Published: 27 February 2013

Abstract

Background

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 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.

Results

Disrupting 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.

Conclusion

Candidate 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.

Keywords:
Genome-wide association study; Drosophila melanogaster; Diabetes mellitus, type 2; Hyperglycemia; Dyslipidemias; Phylogeny; Reverse genetics; High-throughput screening assays; HHEX protein, Human