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Denis Franchimont

Bio: Denis Franchimont is an academic researcher from Université libre de Bruxelles. The author has contributed to research in topics: Inflammatory bowel disease & Crohn's disease. The author has an hindex of 51, co-authored 161 publications receiving 20010 citations. Previous affiliations of Denis Franchimont include National Institutes of Health & University of Liège.


Papers
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Journal ArticleDOI
Luke Jostins1, Stephan Ripke2, Rinse K. Weersma3, Richard H. Duerr4, Dermot P.B. McGovern5, Ken Y. Hui6, James Lee7, L. Philip Schumm8, Yashoda Sharma6, Carl A. Anderson1, Jonah Essers9, Mitja Mitrovic3, Kaida Ning6, Isabelle Cleynen10, Emilie Theatre11, Sarah L. Spain12, Soumya Raychaudhuri9, Philippe Goyette13, Zhi Wei14, Clara Abraham6, Jean-Paul Achkar15, Tariq Ahmad16, Leila Amininejad17, Ashwin N. Ananthakrishnan9, Vibeke Andersen18, Jane M. Andrews19, Leonard Baidoo4, Tobias Balschun20, Peter A. Bampton21, Alain Bitton22, Gabrielle Boucher13, Stephan Brand23, Carsten Büning24, Ariella Cohain25, Sven Cichon26, Mauro D'Amato27, Dirk De Jong3, Kathy L Devaney9, Marla Dubinsky5, Cathryn Edwards28, David Ellinghaus20, Lynnette R. Ferguson29, Denis Franchimont17, Karin Fransen3, Richard B. Gearry30, Michel Georges11, Christian Gieger, Jürgen Glas22, Talin Haritunians5, Ailsa Hart31, Christopher J. Hawkey32, Matija Hedl6, Xinli Hu9, Tom H. Karlsen33, Limas Kupčinskas34, Subra Kugathasan35, Anna Latiano36, Debby Laukens37, Ian C. Lawrance38, Charlie W. Lees39, Edouard Louis11, Gillian Mahy40, John C. Mansfield41, Angharad R. Morgan29, Craig Mowat42, William G. Newman43, Orazio Palmieri36, Cyriel Y. Ponsioen44, Uroš Potočnik45, Natalie J. Prescott6, Miguel Regueiro4, Jerome I. Rotter5, Richard K Russell46, Jeremy D. Sanderson47, Miquel Sans, Jack Satsangi39, Stefan Schreiber20, Lisa A. Simms48, Jurgita Sventoraityte34, Stephan R. Targan, Kent D. Taylor5, Mark Tremelling49, Hein W. Verspaget50, Martine De Vos37, Cisca Wijmenga3, David C. Wilson39, Juliane Winkelmann51, Ramnik J. Xavier9, Sebastian Zeissig20, Bin Zhang25, Clarence K. Zhang6, Hongyu Zhao6, Mark S. Silverberg52, Vito Annese, Hakon Hakonarson53, Steven R. Brant54, Graham L. Radford-Smith55, Christopher G. Mathew12, John D. Rioux13, Eric E. Schadt25, Mark J. Daly2, Andre Franke20, Miles Parkes7, Severine Vermeire10, Jeffrey C. Barrett1, Judy H. Cho6 
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
01 Nov 2012-Nature
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

4,094 citations

Journal ArticleDOI
TL;DR: The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1, which offer promise for informed therapeutic development.
Abstract: Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

2,584 citations

Journal ArticleDOI
Andre Franke1, Dermot P.B. McGovern2, Jeffrey C. Barrett3, Kai Wang4, Graham L. Radford-Smith5, Tariq Ahmad6, Charlie W. Lees7, Tobias Balschun1, James Lee8, Rebecca L. Roberts9, Carl A. Anderson3, Joshua C. Bis10, Suzanne Bumpstead3, David Ellinghaus1, Eleonora M. Festen11, Michel Georges12, Todd Green13, Talin Haritunians2, Luke Jostins3, Anna Latiano14, Christopher G. Mathew15, Grant W. Montgomery5, Natalie J. Prescott15, Soumya Raychaudhuri13, Jerome I. Rotter2, Philip Schumm16, Yashoda Sharma17, Lisa A. Simms5, Kent D. Taylor2, David C. Whiteman5, Cisca Wijmenga11, Robert N. Baldassano4, Murray L. Barclay9, Theodore M. Bayless18, Stephan Brand19, Carsten Büning20, Albert Cohen21, Jean Frederick Colombel22, Mario Cottone, Laura Stronati, Ted Denson23, Martine De Vos24, Renata D'Incà, Marla Dubinsky2, Cathryn Edwards25, Timothy H. Florin26, Denis Franchimont27, Richard B. Gearry9, Jürgen Glas22, Jürgen Glas28, Jürgen Glas19, André Van Gossum27, Stephen L. Guthery29, Jonas Halfvarson30, Hein W. Verspaget31, Jean-Pierre Hugot32, Amir Karban33, Debby Laukens24, Ian C. Lawrance34, Marc Lémann32, Arie Levine35, Cécile Libioulle12, Edouard Louis12, Craig Mowat36, William G. Newman37, Julián Panés, Anne M. Phillips36, Deborah D. Proctor17, Miguel Regueiro38, Richard K Russell39, Paul Rutgeerts40, Jeremy D. Sanderson41, Miquel Sans, Frank Seibold42, A. Hillary Steinhart43, Pieter C. F. Stokkers44, Leif Törkvist45, Gerd A. Kullak-Ublick46, David C. Wilson7, Thomas D. Walters43, Stephan R. Targan2, Steven R. Brant18, John D. Rioux47, Mauro D'Amato45, Rinse K. Weersma11, Subra Kugathasan48, Anne M. Griffiths43, John C. Mansfield49, Severine Vermeire40, Richard H. Duerr38, Mark S. Silverberg43, Jack Satsangi7, Stefan Schreiber1, Judy H. Cho17, Vito Annese14, Hakon Hakonarson4, Mark J. Daly13, Miles Parkes8 
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

2,482 citations

Journal ArticleDOI
Carl A. Anderson1, Gabrielle Boucher2, Charlie W. Lees3, Andre Franke4, Mauro D'Amato5, Kent D. Taylor6, James Lee7, Philippe Goyette2, Marcin Imielinski8, Anna Latiano9, Caroline Lagacé2, Regan Scott10, Leila Amininejad11, Suzannah Bumpstead1, Leonard Baidoo10, Robert N. Baldassano8, Murray L. Barclay12, Theodore M. Bayless13, Stephan Brand14, Carsten Büning15, Jean-Frederic Colombel16, Lee A. Denson17, Martine De Vos18, Marla Dubinsky6, Cathryn Edwards19, David Ellinghaus4, Rudolf S N Fehrmann20, James A B Floyd1, Timothy H. Florin21, Denis Franchimont11, Lude Franke20, Michel Georges22, Jürgen Glas14, Nicole L. Glazer23, Stephen L. Guthery24, Talin Haritunians6, Nicholas K. Hayward25, Jean-Pierre Hugot26, Gilles Jobin2, Debby Laukens18, Ian C. Lawrance27, Marc Lémann26, Arie Levine28, Cécile Libioulle22, Edouard Louis22, Dermot P.B. McGovern6, Monica Milla, Grant W. Montgomery25, Katherine I. Morley1, Craig Mowat29, Aylwin Ng30, William G. Newman31, Roel A. Ophoff32, Laura Papi33, Orazio Palmieri9, Laurent Peyrin-Biroulet, Julián Panés, Anne M. Phillips29, Natalie J. Prescott34, Deborah D. Proctor35, Rebecca L. Roberts12, Richard K Russell36, Paul Rutgeerts37, Jeremy D. Sanderson38, Miquel Sans39, Philip Schumm40, Frank Seibold41, Yashoda Sharma35, Lisa A. Simms25, Mark Seielstad42, Mark Seielstad43, A. Hillary Steinhart44, Stephan R. Targan6, Leonard H. van den Berg32, Morten H. Vatn45, Hein W. Verspaget46, Thomas D. Walters44, Cisca Wijmenga20, David C. Wilson3, Harm-Jan Westra20, Ramnik J. Xavier30, Zhen Zhen Zhao25, Cyriel Y. Ponsioen47, Vibeke Andersen48, Leif Törkvist5, Maria Gazouli49, Nicholas P. Anagnou49, Tom H. Karlsen45, Limas Kupčinskas50, Jurgita Sventoraityte50, John C. Mansfield51, Subra Kugathasan52, Mark S. Silverberg44, Jonas Halfvarson53, Jerome I. Rotter6, Christopher G. Mathew34, Anne M. Griffiths44, Richard B. Gearry12, Tariq Ahmad, Steven R. Brant13, Mathias Chamaillard54, Jack Satsangi3, Judy H. Cho35, Stefan Schreiber4, Mark J. Daly30, Jeffrey C. Barrett1, Miles Parkes7, Vito Annese9, Hakon Hakonarson55, Graham L. Radford-Smith25, Richard H. Duerr10, Severine Vermeire37, Rinse K. Weersma20, John D. Rioux2 
Wellcome Trust Sanger Institute1, Université de Montréal2, University of Edinburgh3, University of Kiel4, Karolinska Institutet5, Cedars-Sinai Medical Center6, University of Cambridge7, University of Pennsylvania8, Casa Sollievo della Sofferenza9, University of Pittsburgh10, Université libre de Bruxelles11, University of Otago12, Johns Hopkins University13, Ludwig Maximilian University of Munich14, Charité15, Lille University of Science and Technology16, Cincinnati Children's Hospital Medical Center17, Ghent University18, Torbay Hospital19, University of Groningen20, Mater Health Services21, University of Liège22, University of Washington23, University of Utah24, QIMR Berghofer Medical Research Institute25, University of Paris26, University of Western Australia27, Tel Aviv University28, University of Dundee29, Harvard University30, University of Manchester31, Utrecht University32, University of Florence33, King's College London34, Yale University35, Royal Hospital for Sick Children36, Katholieke Universiteit Leuven37, Guy's and St Thomas' NHS Foundation Trust38, University of Barcelona39, University of Chicago40, University of Bern41, University of California, San Francisco42, Agency for Science, Technology and Research43, University of Toronto44, University of Oslo45, Leiden University46, University of Amsterdam47, Aarhus University48, National and Kapodistrian University of Athens49, Lithuanian University of Health Sciences50, Newcastle University51, Emory University52, Örebro University53, French Institute of Health and Medical Research54, Center for Applied Genomics55
TL;DR: A meta-analysis of six ulcerative colitis genome-wide association study datasets found many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1.
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

1,291 citations

Journal ArticleDOI
01 Jul 2004-Gut
TL;DR: A novel association of the TLR4 Asp299Gly polymorphism with both Crohn’s disease and UC is reported, which further supports the genetic influence of PRRs in triggering IBD.
Abstract: Background and aims: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn’s disease (CD) and/or ulcerative colitis (UC). Methods: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios. Results: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28–4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24–4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07–3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately. Conclusion: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.

617 citations


Cited by
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Journal ArticleDOI
06 Sep 2012-Nature
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

13,548 citations

Journal ArticleDOI
Paul Burton1, David Clayton2, Lon R. Cardon, Nicholas John Craddock3  +192 moreInstitutions (4)
07 Jun 2007-Nature
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

9,244 citations

Journal Article
01 Jan 2012-Nature
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

8,106 citations

Journal ArticleDOI
08 Oct 2009-Nature
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

7,797 citations

Journal ArticleDOI
01 Nov 2012-Nature
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
Abstract: By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

7,710 citations