title: Two novel type 2 diabetes loci revealed through integration of TCF7L2 DNA occupancy and SNP association data.
abstract: BACKGROUND
  The transcription factor 7-like 2 (TCF7L2) locus is strongly implicated in the pathogenesis of type 2 diabetes (T2D). We previously mapped the genomic regions bound by TCF7L2 using ChIP (chromatin immunoprecipitation)-seq in the colorectal carcinoma cell line, HCT116, revealing an unexpected highly significant over-representation of genome-wide association studies (GWAS) loci associated primarily with endocrine (in particular T2D) and cardiovascular traits.
  
  
  METHODS
  In order to further explore if this observed phenomenon occurs in other cell lines, we carried out ChIP-seq in HepG2 cells and leveraged ENCODE data for five additional cell lines. Given that only a minority of the predicted genetic component to most complex traits has been identified to date, plus our GWAS-related observations with respect to TCF7L2 occupancy, we investigated if restricting association analyses to the genes yielded from this approach, in order to reduce the constraints of multiple testing, could reveal novel T2D loci.
  
  
  RESULTS
  We found strong evidence for the continued enrichment of endocrine and cardiovascular GWAS categories, with additional support for cancer. When investigating all the known GWAS loci bound by TCF7L2 in the shortest gene list, derived from HCT116, the coronary artery disease-associated variant, rs46522 at the UBE2Z-GIP-ATP5G1-SNF8 locus, yielded significant association with T2D within DIAGRAM. Furthermore, when we analyzed tag-SNPs (single nucleotide polymorphisms) in genes not previously implicated by GWAS but bound by TCF7L2 within 5 kb, we observed a significant association of rs4780476 within CPPED1 in DIAGRAM.
  
  
  CONCLUSIONS
  ChIP-seq data generated with this GWAS-implicated transcription factor provided a biologically plausible method to limit multiple testing in the assessment of genome-wide genotyping data to uncover two novel T2D-associated loci.
authors.affiliation: Division of Human Genetics , The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Johnson
authors.affiliation: Division of Human Genetics , The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Genetics and Institute of Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania , USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.affiliation: Division of Human Genetics , The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Deliard
authors.affiliation: Division of Human Genetics , The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA.
authors.forename: Qianghua
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Division of Human Genetics , The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Guy
authors.affiliation: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), Spanish National Research Council (CSIC) , Santander , Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Sainz
authors.affiliation: Department of Genetics and Institute of Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania , USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Pathology and Laboratory Medicine , Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Wells
authors.affiliation: Division of Human Genetics , The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania , USA ; Department of Genetics and Institute of Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania , USA ; Department of Pediatrics , Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania , USA.
authors.forename: Struan F A
authors.identifier: 0000-0003-2025-5302
authors.initials: SF
authors.lastname: Grant
keywords: Gene; Genetic Association; Transcription Factor; Type 2