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 Pendse, Prasanna V. Ramachandran, Jianbo Na, Narisu Narisu, Jill L. Fink, Ross L. Cagan, Francis S. Collins, Thomas J. Baranski

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Article number136
JournalBMC genomics
Volume14
Issue number1
DOIs
StatePublished - Feb 27 2013

Keywords

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

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