Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Aleksejs Sazonovs; Christine R Stevens; Guhan R Venkataraman; Kai Yuan; Brandon Avila; Maria T Abreu; Tariq Ahmad; Matthieu Allez; Ashwin N Ananthakrishnan; Gil Atzmon; Aris Baras; Jeffrey C Barrett; Nir Barzilai; Laurent Beaugerie; Ashley Beecham; Charles N Bernstein; Alain Bitton; Bernd Bokemeyer; Andrew Chan; Daniel Chung; Isabelle Cleynen; Jacques Cosnes; David J Cutler; Allan Daly; Oriana M Damas; Lisa W Datta; Noor Dawany; Marcella Devoto; Sheila Dodge; Eva Ellinghaus; Laura Fachal; Martti Farkkila; William Faubion; Manuel Ferreira; Denis Franchimont; Stacey B Gabriel; Tian Ge; Michel Georges; Kyle Gettler; Mamta Giri; Benjamin Glaser; Siegfried Goerg; Philippe Goyette; Daniel Graham; Eija Hämäläinen; Talin Haritunians; Graham A Heap; Mikko Hiltunen; Marc Hoeppner; Julie E Horowitz; Peter Irving; Vivek Iyer; Chaim Jalas; Judith Kelsen; Hamed Khalili; Barbara S Kirschner; Kimmo Kontula; Jukka T Koskela; Subra Kugathasan; Juozas Kupcinskas; Christopher A Lamb; Matthias Laudes; Chloé Lévesque; Adam P Levine; James D Lewis; Claire Liefferinckx; Britt-Sabina Loescher; Edouard Louis; John Mansfield; Sandra May; Jacob L McCauley; Emebet Mengesha; Myriam Mni; Paul Moayyedi; Christopher J Moran; Rodney D Newberry; Sirimon O'Charoen; David T Okou; Bas Oldenburg; Harry Ostrer; Aarno Palotie; Jean Paquette; Joel Pekow; Inga Peter; Marieke J Pierik; Cyriel Y Ponsioen; Nikolas Pontikos; Natalie Prescott; Ann E Pulver; Souad Rahmouni; Daniel L Rice; Päivi Saavalainen; Bruce Sands; R Balfour Sartor; Elena R Schiff; Stefan Schreiber; L Philip Schumm; Anthony W Segal; Philippe Seksik; Rasha Shawky; Shehzad Z Sheikh; Mark S Silverberg; Alison Simmons; Jurgita Skeiceviciene; Harry Sokol; Matthew Solomonson; Hari Somineni; Dylan Sun; Stephan Targan; Dan Turner; Holm H Uhlig; Andrea E van der Meulen; Séverine Vermeire; Sare Verstockt; Michiel D Voskuil; Harland S Winter; Justine Young; Richard H Duerr; Andre Franke; Steven R Brant; Judy Cho; Rinse K Weersma; Miles Parkes; Ramnik J Xavier; Manuel A Rivas; John D Rioux; Dermot P B McGovern; Hailiang Huang; Carl A Anderson; Mark J Daly; International IBD Genetics Consortium

doi:10.1038/s41588-022-01156-2

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Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Journal article

Peer reviewed

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Aleksejs Sazonovs, Christine R Stevens, Guhan R Venkataraman, Kai Yuan, Brandon Avila, Maria T Abreu, Tariq Ahmad, Matthieu Allez, Ashwin N Ananthakrishnan, Gil Atzmon, …

Nature genetics, Vol.54(9), pp.1275-1283

01/09/2022

DOI: https://doi.org/10.1038/s41588-022-01156-2

PMID: 36038634

Abstract

Crohn Disease - genetics

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Polymorphism, Single Nucleotide - genetics

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

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Title: Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility
Creators - without role: Aleksejs Sazonovs - Wellcome Sanger Institute
Christine R Stevens - Massachusetts General Hospital
Guhan R Venkataraman - Stanford University
Kai Yuan - Massachusetts General Hospital
Brandon Avila - Broad Institute
Maria T Abreu - University of Miami
Tariq Ahmad - Royal Devon and Exeter Hospital
Matthieu Allez - Hôpital Saint-Louis
Ashwin N Ananthakrishnan - Massachusetts General Hospital
Gil Atzmon - Albert Einstein College of Medicine
Aris Baras - Regeneron
Jeffrey C Barrett - Wellcome Sanger Institute
Nir Barzilai - Yeshiva University
Laurent Beaugerie - Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
Ashley Beecham - University of Miami
Charles N Bernstein - University of Manitoba
Alain Bitton - McGill University Health Centre
Bernd Bokemeyer - Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
Andrew Chan - Brigham and Women's Hospital
Daniel Chung - Massachusetts General Hospital
Isabelle Cleynen - KU Leuven
Jacques Cosnes - Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France
David J Cutler - Emory University School of Medicine
Allan Daly - Wellcome Sanger Institute
Oriana M Damas - University of Miami
Lisa W Datta - Johns Hopkins University School of Medicine
Noor Dawany - Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
Marcella Devoto - University of Pennsylvania
Sheila Dodge - Broad Institute
Eva Ellinghaus - Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
Laura Fachal - Wellcome Sanger Institute
Martti Farkkila - Helsinki University Central Hospital, Helsinki, Finland
William Faubion - Mayo Clinic, Rochester, Rochester, MN, USA
Manuel Ferreira - Regeneron
Denis Franchimont - Erasme Hospital, ULB, Brussels, Belgium
Stacey B Gabriel - Broad Institute
Tian Ge - Massachusetts General Hospital
Michel Georges - University of Liège
Kyle Gettler - Icahn School of Medicine at Mount Sinai
Mamta Giri - Icahn School of Medicine at Mount Sinai
Benjamin Glaser - Hebrew University of Jerusalem
Siegfried Goerg - University Medical Center Schleswig-Holstein, Kiel, Germany
Philippe Goyette - Montreal Heart Institute
Daniel Graham - Massachusetts General Hospital
Eija Hämäläinen - University of Helsinki
Talin Haritunians - Cedars-Sinai Medical Center
Graham A Heap - Royal Devon and Exeter Hospital
Mikko Hiltunen - University of Eastern Finland
Marc Hoeppner - Christian-Albrechts-University of Kiel, Kiel, Germany
Julie E Horowitz - Regeneron
Peter Irving - School of Immunology and Microbial Sciences, Kings College London, London, UK
Vivek Iyer - Wellcome Sanger Institute
Chaim Jalas - Director of Genetic Resources and Services, Center for Rare Jewish Genetic Disorders, Bonei Olam, Brooklyn, NY, USA
Judith Kelsen - Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
Hamed Khalili - Massachusetts General Hospital
Barbara S Kirschner - University of Chicago
Kimmo Kontula - Helsinki University Hospital
Jukka T Koskela - University of Helsinki
Subra Kugathasan - Emory University School of Medicine
Juozas Kupcinskas - Lithuanian University of Health Sciences
Christopher A Lamb - Newcastle upon Tyne Hospitals NHS Foundation Trust
Matthias Laudes - University Medical Center Schleswig-Holstein, Kiel, Germany
Chloé Lévesque - Montreal Heart Institute
Adam P Levine - University College London, London, UK
James D Lewis - Crohn's and Colitis Foundation
Claire Liefferinckx - Erasme Hospital, ULB, Brussels, Belgium
Britt-Sabina Loescher - Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
Edouard Louis - University of Liège
John Mansfield - Newcastle upon Tyne Hospitals NHS Foundation Trust
Sandra May - Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
Jacob L McCauley - University of Miami
Emebet Mengesha - Cedars-Sinai Medical Center
Myriam Mni - University of Liège
Paul Moayyedi - McMaster University
Christopher J Moran - Massachusetts General Hospital
Rodney D Newberry - Washington University School of Medicine, St. Louis, MO, USA
Sirimon O'Charoen - Crohn's and Colitis Foundation
David T Okou - Institut National de Sante Publique (INSP), Abidjan, Côte d'Ivoire
Bas Oldenburg - Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
Harry Ostrer - Albert Einstein College of Medicine
Aarno Palotie - Massachusetts General Hospital
Jean Paquette - Montreal Heart Institute
Joel Pekow - University of Chicago
Inga Peter - Icahn School of Medicine at Mount Sinai
Marieke J Pierik - Maastricht University Medical Centre
Cyriel Y Ponsioen - Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
Nikolas Pontikos - University College London, London, UK
Natalie Prescott - Department of Medical and Molecular Genetics, Kings College London, London, UK
Ann E Pulver - Johns Hopkins University
Souad Rahmouni - University of Liège
Daniel L Rice - Wellcome Sanger Institute
Päivi Saavalainen - University of Helsinki
Bruce Sands - Icahn School of Medicine at Mount Sinai
R Balfour Sartor - University of North Carolina School of Medicine
Elena R Schiff - University College London, London, UK
Stefan Schreiber - Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
L Philip Schumm - University of Chicago
Anthony W Segal - University College London
Philippe Seksik - Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
Rasha Shawky - Cambridge University Hospitals NHS Foundation Trust
Shehzad Z Sheikh - University of North Carolina School of Medicine
Mark S Silverberg - Mount Sinai Hospital
Alison Simmons - University of Oxford
Jurgita Skeiceviciene - Lithuanian University of Health Sciences
Harry Sokol - Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
Matthew Solomonson - Broad Institute
Hari Somineni - Emory University School of Medicine
Dylan Sun - Regeneron
Stephan Targan - Cedars-Sinai Medical Center
Dan Turner - Shaare Zedek Medical Center, Jerusalem, Israel
Holm H Uhlig - John Radcliffe Hospital
Andrea E van der Meulen - Leiden University Medical Center
Séverine Vermeire - KU Leuven
Sare Verstockt - KU Leuven
Michiel D Voskuil - University Medical Center Groningen
Harland S Winter - Massachusetts General Hospital
Justine Young - Crohn's and Colitis Foundation
Richard H Duerr - University of Pittsburgh
Andre Franke - Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
Steven R Brant - University of New Brunswick
Judy Cho - Icahn School of Medicine at Mount Sinai
Rinse K Weersma - University Medical Center Groningen
Miles Parkes - Cambridge University Hospitals NHS Foundation Trust
Ramnik J Xavier - Massachusetts Institute of Technology
Manuel A Rivas - Stanford University
John D Rioux - Université de Montréal
Dermot P B McGovern - Cedars-Sinai Medical Center
Hailiang Huang - Massachusetts General Hospital
Carl A Anderson - Wellcome Sanger Institute
Mark J Daly - University of Helsinki
International IBD Genetics Consortium
Publication Details: Nature genetics, Vol.54(9), pp.1275-1283
Grant note: P01 DK094779 / NIDDK NIH HHS Department of Health Wellcome Trust MR/S036377/1 / Medical Research Council MR/M00533X/1 / Medical Research Council U01 DK062413 / NIDDK NIH HHS K23 DK117054 / NIDDK NIH HHS MC_UU_12010/7 / Medical Research Council P01 DK046763 / NIDDK NIH HHS UM1 HG008895 / NHGRI NIH HHS U01 DK062431 / NIDDK NIH HHS 206194 / Wellcome Trust U01 DK062423 / NIDDK NIH HHS P30 AG038072 / NIA NIH HHS MC_PC_MR/S025952/1 / Medical Research Council U01 DK062420 / NIDDK NIH HHS R01 DK111843 / NIDDK NIH HHS 108413/A/15/D / Wellcome Trust U01 HG009080 / NHGRI NIH HHS U54 HG003067 / NHGRI NIH HHS R01 HG010140 / NHGRI NIH HHS R01 DK104844 / NIDDK NIH HHS P30 DK043351 / NIDDK NIH HHS K01 DK114379 / NIDDK NIH HHS MC_UU_00008/7 / Medical Research Council U01 DK062432 / NIDDK NIH HHS R01 DK087694 / NIDDK NIH HHS
Identifiers: 9925793608331
Academic Unit: Prince Sattam Bin Abdulaziz University
Language: English
Resource Type: Journal article