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Nature Genetics, November 2011, Volume 43, Number 11

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

Manuel A Rivas, Mélissa Beaudoin, Agnes Gardet, Christine Stevens, Yashoda Sharma, Clarence K Zhang, Gabrielle Boucher, Stephan Ripke, David Ellinghaus, Noel Burtt, Tim Fennell, Andrew Kirby, Anna Latiano, Philippe Goyette, Todd Green, Jonas Halfvarson, Talin Haritunians, Joshua M Korn, Finny Kuruvilla, Caroline Lagacé, Benjamin Neale, Ken Sin Lo, Phil Schumm, Leif Törkvist, National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC), United Kingdom Inflammatory Bowel Disease Genetics Consortium, International Inflammatory Bowel Disease Genetics Consortium, Marla C Dubinsky, Steven R Brant, Mark S Silverberg, Richard H Duerr, David Altshuler, Stacey Gabriel, Guillaume Lettre, Andre Franke, Mauro D'Amato, Dermot P B McGovern, Judy H Cho, John D Rioux, Ramnik J Xavier & Mark J Daly

abstract

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn’s disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn’s disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10−16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. 

We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

LIST OF PARTICIPANTS

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1. BE-SMART | 2. CEDAR-UC | 3. COMBINED THERAPY OF BIOLOGICALS AND NEW ORAL DRUGS. | 4. DETECT | 5. DNA BANKING | 6. GENGISCAN | 7. HELP-AID | 8. I-CARE | 9. IMMUNIZATION | 10. LOVE | 11. PACIFIC | 12. PEDIATRIC | 13. SPARE
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- - x x x x
Leila Amininejad x x x
Saskia Appelmans
Filip Baert x x x x x x
Thomas Billiet
Patrick Bontems
Peter Bossuyt x x x x x x
Guillaume Burnet
Peter Burvenich
Philippe Caenepeel
Olivier Cajot
Christophe Claessens x
Jean-Charles Coche
Jean-Louis Coenegrachts
Arnaud Colard x
Filip Couturier
Anneline Cremer x x
Cléo Croonen
Francois D'Heygere x
Steven De Coninck
Elisabeth De Greef x
Marc De Maeyer
Marc De Reuck
Elodie De Ruyck
Nicolas de Suray
Martine De Vos x x x x
Benedicte De Vroey
Stefan Delen
Marie-Armelle Denis
Pieter Dewint x x
Olivier Dewit x x x
Sophie Dewit x x
Joris Dutre
Marc Etienne
Marc Ferrante x x x x x
René Fiasse
Fernand Fontaine x x
Denis Franchimont x x x x x x
Pieter Hindryckx x
Ilse Hoffman
Evelien Humblet x
Saskia Ilegems
Guy Lambrecht x x x
Pierre Lammens
Claire Liefferinckx x
Triana Lobaton
Edouard Louis x x x x x
Elisabeth Macken x
Marie-Christine Mairlot
Jean-Marc Maisin
Fazia Mana x
Walter Margos
Fady Mokaddem
Kim Moubax
Vinciane Muls
Carmen Musala
Michele Ngassa
Maja Noman
Hanne Ooms
An Outtier
Romy Ouziel
Harald Peeters
Annelies Posen
Philippe Potvin
Lieven Pouillon
Jean-Francois Rahier x x x x x x
Catherine Reenaers x x x
João Sabino
Michael Schapira
Nathalie Schoofs
Nele Schoofs
Alexandra Sermeus
Francoise Smets
Michaël Somers
Dirk Staessen
Marjan Steppe
Beatrijs Strubbe x
Jo Swinnen
Clara Thienpont
Haydeh Vafa
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Jurgen Van Dongen
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Philippe Van Hootegem x x
Catherine Van Kemseke
Wouter Van Moerkercke x x x
Steven Van Outryve
Stijn Vanden Branden x x x x
Jo Vandervoort
Gigi Veereman x
Severine Vermeire x x x
Annelies Verreth
Bram Verstockt
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