title: Genome-wide analyses of ChIP-Seq derived FOXA2 DNA occupancy in liver points to genetic networks underpinning multiple complex traits.
abstract: BACKGROUND
  Forkhead Box A2 (FOXA2) exerts an influence on glucose homeostasis via activity in the liver. In addition, a key genome-wide association study (GWAS) recently demonstrated that genetic variation, namely rs6048205, at the FOXA2 locus is robustly associated with fasting glucose levels. Our hypothesis was that this DNA-binding protein regulates the expression of a set of molecular pathways critical to endocrine traits.
  
  
  METHODS
  Drawing on our laboratory and bioinformatic experience with chromatin immunoprecipitation followed by massively parallel sequencing, we analyzed our existing FOXA2 chromatin immunoprecipitation followed by massively parallel sequencing data generated in human liver, using the algorithm hypergeometric optimization of motif enrichment, to gain insight into its global genomic binding pattern from a disease perspective.
  
  
  RESULTS
  We performed a pathway analysis of the gene list using the gene set enrichment analysis algorithm, which yielded a number of significant annotations. Motivated by the fact that the FOXA2 locus has been implicated by GWAS, we cross-referenced the occupancy sites with the National Institutes of Health GWAS catalog and found strong evidence for the enrichment of loci implicated in endocrine, neuropsychiatric, cardiovascular, and cancer trait categories, but interestingly there was no evidence for enrichment for inflammation related traits. Intriguingly, a FOXA2 occupancy site coincided with rs6048205, suggesting that this variant confers its effect, at least partially, via a perturbation of a FOXA2 feedback mechanism.
  
  
  CONCLUSIONS
  Our data strongly suggest that FOXA2 is acting as a master regulator of key pathways that are enriched for loci implicated by GWAS for most trait categories, with the clear exception of inflammation, suggesting that this factor exerts its effect in this context via noninflammatory processes.
authors.affiliation: Division of Human Genetics (M.E.J., S.F.A.G.) and Department of Pathology and Laboratory Medicine (A.D.W.), The Children's Hospital of Philadelphia, and Department of Genetics and Institute of Diabetes, Obesity, and Metabolism (J.S., K.H.K., S.F.A.G.), and Department of Pediatrics (S.F.A.G.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Johnson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Wells
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D004700:Endocrine System Diseases / Q000235:genetics; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D001523:Mental Disorders / Q000235:genetics; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D040641:Quantitative Trait Loci
chemical_list: C496502:FOXA2 protein, human; D051542:Hepatocyte Nuclear Factor 3-beta; D004247:DNA