title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Developmental and Regenerative Biology, Mount SinaiSchool of Medicine, New York, NY, USA.
authors: Jay
authors: J
authors: Pendse
authors: Prasanna V
authors: PV
authors: Ramachandran
authors: Jianbo
authors: J
authors: Na
authors: Narisu
authors: N
authors: Narisu
authors: Jill L
authors: JL
authors: Fink
authors: Ross L
authors: RL
authors: Cagan
authors: Francis S
authors: FS
authors: Collins
authors: Thomas J
authors: TJ
authors: Baranski
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005216:Fat Body / Q000378:metabolism / Q000473:pathology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D009928:Organ Specificity; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; C109229:ko protein, Drosophila; D005947:Glucose