AIMS/HYPOTHESIS: Recent functional characterisations of genome-wide association study (GWAS) loci suggest that cis-regulatory variation may be a common paradigm for complex disease susceptibility. Several studies point to a similar mechanism at the transcription factor 7-like 2 (TCF7L2) GWAS locus for type 2 diabetes. To address this possibility, we carried out an in vitro scan of this diabetes-associated locus to fine-map cis-regulatory sequences within this genomic interval. METHODS: A systematic cell-based enhancer strategy was employed to interrogate all sequences within the 92 kb type-2-diabetes-association interval for cis-regulatory activity in a panel of cell lines (HCT-116, Neuro-2a, C2C12, U2OS, MIN6 and HepG2). We further evaluated chromatin state at a subset of these regions in HCT-116 and U2OS cells and examined allelic-specific enhancer properties at the type-2-diabetes-associated single nucleotide polymorphism (SNP) rs7903146. RESULTS: In total, we assigned cis-regulatory activity to approximately 30% (9/28) of constructs tested. Notably, a subset of enhancers was active across multiple cell lines and overlapped with key epigenetic markers suggestive of cis-regulatory sequences. We further replicated the allelic-specific properties for SNP rs7903146 in pancreatic beta cells and additionally demonstrate identical allelic-specific enhancer effects in other cell lines. CONCLUSIONS: These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.
AIMS/HYPOTHESIS: Recent functional characterisations of genome-wide association study (GWAS) loci suggest that cis-regulatory variation may be a common paradigm for complex disease susceptibility. Several studies point to a similar mechanism at the transcription factor 7-like 2 (TCF7L2) GWAS locus for type 2 diabetes. To address this possibility, we carried out an in vitro scan of this diabetes-associated locus to fine-map cis-regulatory sequences within this genomic interval. METHODS: A systematic cell-based enhancer strategy was employed to interrogate all sequences within the 92 kb type-2-diabetes-association interval for cis-regulatory activity in a panel of cell lines (HCT-116, Neuro-2a, C2C12, U2OS, MIN6 and HepG2). We further evaluated chromatin state at a subset of these regions in HCT-116 and U2OS cells and examined allelic-specific enhancer properties at the type-2-diabetes-associated single nucleotide polymorphism (SNP) rs7903146. RESULTS: In total, we assigned cis-regulatory activity to approximately 30% (9/28) of constructs tested. Notably, a subset of enhancers was active across multiple cell lines and overlapped with key epigenetic markers suggestive of cis-regulatory sequences. We further replicated the allelic-specific properties for SNP rs7903146 in pancreatic beta cells and additionally demonstrate identical allelic-specific enhancer effects in other cell lines. CONCLUSIONS: These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.
Authors: Michael L Stitzel; Praveen Sethupathy; Daniel S Pearson; Peter S Chines; Lingyun Song; Michael R Erdos; Ryan Welch; Stephen C J Parker; Alan P Boyle; Laura J Scott; Elliott H Margulies; Michael Boehnke; Terrence S Furey; Gregory E Crawford; Francis S Collins Journal: Cell Metab Date: 2010-11-03 Impact factor: 27.287
Authors: Thomas Hansen; Andrés Ingason; Srdjan Djurovic; Ingrid Melle; Mogens Fenger; Omar Gustafsson; Klaus D Jakobsen; Henrik B Rasmussen; Sarah Tosato; Marcella Rietschel; Josef Frank; Mike Owen; Chiara Bonetto; Jaana Suvisaari; Johan Hilge Thygesen; Hannes Pétursson; Jouko Lönnqvist; Engilbert Sigurdsson; Ina Giegling; Nick Craddock; Michael C O'Donovan; Mirella Ruggeri; Sven Cichon; Roel A Ophoff; Olli Pietiläinen; Leena Peltonen; Markus M Nöthen; Dan Rujescu; David St Clair; David A Collier; Ole A Andreassen; Thomas Werge Journal: Biol Psychiatry Date: 2011-03-16 Impact factor: 13.382
Authors: Kyle J Gaulton; Takao Nammo; Lorenzo Pasquali; Jeremy M Simon; Paul G Giresi; Marie P Fogarty; Tami M Panhuis; Piotr Mieczkowski; Antonio Secchi; Domenico Bosco; Thierry Berney; Eduard Montanya; Karen L Mohlke; Jason D Lieb; Jorge Ferrer Journal: Nat Genet Date: 2010-01-31 Impact factor: 38.330
Authors: Aaron R Folsom; James S Pankow; James M Peacock; Suzette J Bielinski; Gerardo Heiss; Eric Boerwinkle Journal: Diabetes Care Date: 2008-02-11 Impact factor: 19.112
Authors: Stéphane Cauchi; Younes El Achhab; Hélène Choquet; Christian Dina; Franz Krempler; Raimund Weitgasser; Chakib Nejjari; Wolfgang Patsch; Mohamed Chikri; David Meyre; Philippe Froguel Journal: J Mol Med (Berl) Date: 2007-05-03 Impact factor: 5.606
Authors: André Gustavo P Sousa; Guilherme F Marquezine; Pedro A Lemos; Eulogio Martinez; Neuza Lopes; Whady A Hueb; José E Krieger; Alexandre C Pereira Journal: PLoS One Date: 2009-11-17 Impact factor: 3.240
Authors: Qianghua Xia; Sandra Deliard; Chao-Xing Yuan; Matthew E Johnson; Struan F A Grant Journal: Eur J Hum Genet Date: 2014-03-26 Impact factor: 4.246
Authors: Kathleen A Bailey; Daniel Savic; Mark Zielinski; Soo-Young Park; Ling-Jia Wang; Piotr Witkowski; Matthew Brady; Manami Hara; Graeme I Bell; Marcelo A Nobrega Journal: Hum Mol Genet Date: 2014-11-14 Impact factor: 6.150