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 Hamalainen; 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; Chloe Levesque; 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; Paivi 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; Severine 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; Belgium IBD 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.1275-3

2022-09-01

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

PMID: 36038634

Appears in Miller School of Medicine - Latest Publications

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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. Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.120 Inflammatory Bowel Diseases & Infections; 1.120.139 Ulcerative Colitis
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility
Creators: Aleksejs Sazonovs - Wellcome Sanger Institute
Christine R. Stevens - Broad Institute
Guhan R. Venkataraman - Stanford University
Kai Yuan - Broad Institute
Brandon Avila - Broad Institute
Maria T. Abreu - University of Miami
Tariq Ahmad - Phillips Exeter Academy
Matthieu Allez - Université Paris Cité
Ashwin N. Ananthakrishnan - Massachusetts Gen Hosp, Crohns & Colitis Ctr, Div Gastroenterol, Boston, MA USA
Gil Atzmon - University of Haifa
Aris Baras - Regeneron
Jeffrey C. Barrett - Wellcome Genome Campus
Nir Barzilai - Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA
Laurent Beaugerie - Sorbonne Université
Ashley Beecham - University of Miami
Charles N. Bernstein - University of Manitoba
Alain Bitton - McGill University
Bernd Bokemeyer - College Station Medical Center
Andrew Chan - Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA
Daniel Chung - Massachusetts Gen Hosp, Boston, MA 02114 USA
Isabelle Cleynen - KU Leuven
Jacques Cosnes - Assistance Publique – Hôpitaux de Paris
David J. Cutler - Emory University
Allan Daly - Wellcome Genome Campus
Oriana M. Damas - University of Miami
Lisa W. Datta - Johns Hopkins University
Noor Dawany - Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
Marcella Devoto - Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
Sheila Dodge - Broad Institute
Eva Ellinghaus - Christian Albrechts Univ Kiel, Kiel, Germany
Laura Fachal - Wellcome Genome Campus
Martti Farkkila - Helsinki Univ Cent Hosp, Helsinki, Finland
William Faubion - Mayo Clin, Rochester, MN USA
Manuel Ferreira - Regeneron
Denis Franchimont - ULB, Erasme Hosp, Brussels, Belgium
Stacey B. Gabriel - Broad Institute
Tian Ge - Broad Institute
Michel Georges - University of Liège
Kyle Gettler - Supreme Council Of Health
Mamta Giri - Supreme Council Of Health
Benjamin Glaser - Hadassah
Siegfried Goerg - College Station Medical Center
Philippe Goyette - Montreal Heart Institute
Daniel Graham - Broad Institute
Eija Hamalainen - University of Helsinki
Talin Haritunians - College Station Medical Center
Graham A. Heap - Phillips Exeter Academy
Mikko Hiltunen - University of Eastern Finland
Marc Hoeppner - Christian Albrechts Univ Kiel, Kiel, Germany
Julie E. Horowitz - Regeneron
Peter Irving - Guys & St Thomas Hosp, Dept Gastroenterol, London, England
Vivek Iyer - Wellcome Genome Campus
Chaim Jalas - Bonei Olam, Genet Resources & Serv, Ctr Rare Jewish Genet Disorders, Brooklyn, NY USA
Judith Kelsen - Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
Hamed Khalili - Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA
Barbara S. Kirschner - University of Chicago
Kimmo Kontula - University of Helsinki
Jukka T. Koskela - University of Helsinki
Subra Kugathasan - Emory University
Juozas Kupcinskas - Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania
Christopher A. Lamb - Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Matthias Laudes - College Station Medical Center
Chloe Levesque - Montreal Heart Institute
Adam P. Levine - UCL, London, England
James D. Lewis - Supreme Council Of Health
Claire Liefferinckx - ULB, Erasme Hosp, Brussels, Belgium
Britt-Sabina Loescher - Christian Albrechts Univ Kiel, Kiel, Germany
Edouard Louis - University of Liège
John Mansfield - Newcastle University
Sandra May - Christian Albrechts Univ Kiel, Kiel, Germany
Jacob L. McCauley - University of Miami
Emebet Mengesha - College Station Medical Center
Myriam Mni - University of Liège
Paul Moayyedi - McMaster University
Christopher J. Moran - Massachusetts Gen Hosp, Boston, MA 02114 USA
Rodney D. Newberry - Supreme Council Of Health
Sirimon O'Charoen - Crohns & Colitis Fdn, New York, NY USA
David T. Okou - Emory University
Bas Oldenburg - College Station Medical Center
Harry Ostrer - Albert Einstein Coll Med, Bronx, NY 10467 USA
Aarno Palotie - Broad Institute
Jean Paquette - Montreal Heart Institute
Joel Pekow - University of Chicago
Inga Peter - Supreme Council Of Health
Marieke J. Pierik - Maastricht University
Cyriel Y. Ponsioen - College Station Medical Center
Nikolas Pontikos - UCL, London, England
Natalie Prescott - College Station Medical Center
Ann E. Pulver - Johns Hopkins University
Souad Rahmouni - University of Liège
Daniel L. Rice - Wellcome Genome Campus
Paivi Saavalainen - University of Helsinki
Bruce Sands - Supreme Council Of Health
R. Balfour Sartor - Supreme Council Of Health
Elena R. Schiff - UCL, London, England
Stefan Schreiber - Christian Albrechts Univ Kiel, Kiel, Germany
L. Philip Schumm - University of Chicago
Anthony W. Segal - UCL, London, England
Philippe Seksik - Sorbonne Université
Rasha Shawky - University of Cambridge
Shehzad Z. Sheikh - Supreme Council Of Health
Mark S. Silverberg - Mt Sinai Hosp, Toronto, ON, Canada
Alison Simmons - University of Oxford
Jurgita Skeiceviciene - Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania
Harry Sokol - Sorbonne Université
Matthew Solomonson - Broad Institute
Hari Somineni - Childrens Healthcare Atlanta, Atlanta, GA USA
Dylan Sun - Regeneron
Stephan Targan - College Station Medical Center
Dan Turner - College Station Medical Center
Holm H. Uhlig - University of Oxford
Andrea E. van der Meulen - Leiden University
Severine Vermeire - Univ Hosp Leuven, Leuven, Belgium
Sare Verstockt - KU Leuven
Michiel D. Voskuil - University of Groningen
Harland S. Winter - Massachusetts Gen Hosp, Boston, MA 02114 USA
Justine Young - Crohns & Colitis Fdn, New York, NY USA
Richard H. Duerr - University of Pittsburgh
Andre Franke - Christian Albrechts Univ Kiel, Kiel, Germany
Steven R. Brant - Johns Hopkins University
Judy Cho - Supreme Council Of Health
Rinse K. Weersma - University of Groningen
Miles Parkes - University of Cambridge
Ramnik J. Xavier - Broad Institute
Manuel A. Rivas - Stanford University
John D. Rioux - Montreal Heart Institute
Dermot P. B. McGovern - College Station Medical Center
Hailiang Huang - Broad Institute
Carl A. Anderson - Wellcome Genome Campus
Mark J. Daly - Broad Institute
Belgium IBD Consortium
Publication Details: Nature genetics, Vol.54(9), pp.1275-3
Publisher: NATURE PORTFOLIO
Number of pages: 22
Grant note: B. Hasso Family Foundation 5U01HG009080 / NIH Center for Multi-and Trans-ethnic Mapping of Mendelian and Complex Diseases K01DK114379; P30DK043351; P01DK046763; U01DK062413; R01DK104844 / NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Martin Schlaff, James Brooks R01HG010140 / NHGRI of the NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) 2015PG-IBD001 / Leona M. & Harry B. Helmsley Charitable Trust Stanley Center for Psychiatric Research U54HG003067; 5UM1HG008895 / US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA NIHR Oxford Biomedical Research Centre; National Institute for Health Research (NIHR) Leona M. and Harry B. Helmsley Charitable Trust 206194; 108413/A/15/D / Wellcome Trust R01HG010140; 5U01HG009080; DK062431; DK062432; DK087694; K23DK117054; R01DK111843; P01DK094779; DK062420 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 312074; 336824 / Academy of Finland Centre of Excellence in Complex Disease Genetics; Academy of Finland
Academic Unit: Miller School of Medicine; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); John P. Hussman Institute for Human Genomics; UMMG Dept of Medicine - Gastroenterology
Language: English
Resource Type: Journal article
PMID: 36038634
Record Identifier: 991031757833202976