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

Belgium IBD Consortium

doi:10.1038/s41588-022-01156-2

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

Belgium IBD Consortium

Babraham Institute; Wellcome Sanger Institute
Wellcome Trust Sanger Institute; University of Helsinki; The Broad Institute of MIT and Harvard
University of Ioannina School of Medicine; Stanford Prevention Research Center; Stanford University School of Medicine
University of Miami Brain Endowment Bank, Miami, FL, 33136, USA.
Royal Devon and Exeter Hospital
University of Paris VII - Denis Diderot University
Crohn's and Colitis Center
Univ Haifa, International Business Machines (IBM), University of Haifa, IBM Haifa Res Labs
Division of Endocrinology, Diabetes, and Nutrition, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; The Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, USA.
AP-HP Hospital Saint Antoine
University of Manitoba
McGill University
University Medical Center Schleswig-Holstein
Massachusetts General Hospital
Department of Human Genetics and Department of Clinical Genetics
Institut Curie, Department of Tumour Biology, Paris, France28Institut Curie, INSERM U830, Paris, France29Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
is with Emory University
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cognitive Science Department, Johns Hopkins University, Baltimore, MD USA.
Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Vasa Central Hospital, Vasa, Finland; Folkhälsan Research Centre, Helsinki, Finland; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
Mayo Clinic Libraries, Mayo Clinic, Jacksonville, FL 32224, USA
Erasme UnCiversity Hospital
Department of Psychology, University of Liège, Liège, Belgium.
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
R.H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Medicine, Université de Montréal and Research Center, Montreal Heart Institute, Montreal, QC, Canada.
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
University of Eastern Finland
Gastroenterology Department
GSTT Guy's and St Thomas' NHS Foundation Trust
School of Immunology and Microbial Sciences and School of Life Course Sciences
Kings Coll London, Kings College London, University of London School of Pharmacy, University College London, University of London, Sch Pharm
Department Medical and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

137 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1275-1283
Number of pages	9
Journal	Nature genetics
Volume	54
Issue number	9
Early online date	29 Aug 2022
DOIs	https://doi.org/10.1038/s41588-022-01156-2
Publication status	Published - Sept 2022

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10.1038/s41588-022-01156-2

Cite this

@article{1f7584430e3f4dfba2cd739aff7e1007,

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

abstract = "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.",

author = "Aleksejs Sazonovs and Stevens, \{Christine R\} and Venkataraman, \{Guhan R\} and Kai Yuan and Brandon Avila and Abreu, \{Maria T\} and Tariq Ahmad and Matthieu Allez and Ananthakrishnan, \{Ashwin N\} and Gil Atzmon and Aris Baras and Barrett, \{Jeffrey C\} and Nir Barzilai and Laurent Beaugerie and Ashley Beecham and Bernstein, \{Charles N\} and Alain Bitton and Bernd Bokemeyer and Andrew Chan and Daniel Chung and Isabelle Cleynen and Jacques Cosnes and Cutler, \{David J\} and Allan Daly and Damas, \{Oriana M\} and Datta, \{Lisa W\} and Noor Dawany and Marcella Devoto and Sheila Dodge and Eva Ellinghaus and Laura Fachal and Martti Farkkila and William Faubion and Manuel Ferreira and Denis Franchimont and Gabriel, \{Stacey B\} and Tian Ge and Michel Georges and Kyle Gettler and Mamta Giri and Benjamin Glaser and Siegfried Goerg and Philippe Goyette and Daniel Graham and Eija H{\"a}m{\"a}l{\"a}inen and Talin Haritunians and Heap, \{Graham A\} and Mikko Hiltunen and Peter Irving and Natalie Prescott and \{Belgium IBD Consortium\}",

note = "Funding Information: We thank all of the principal investigators, local staff from individual cohorts and all of the patients who kindly donated samples used in the study for making possible this global collaboration and resource to advance IBD genetics research. This research was funded in whole, or in part, by the US National Institutes of Health grants no. U54HG003067 and no. 5UM1HG008895, the Wellcome Trust grants no. 206194 and no. 108413/A/15/D, and The Leona M. \& Harry B. Helmsley Charitable Trust grant no. 2015PG-IBD001. We thank the Broad Institute Genomics Platform for genomic data generation efforts and the Stanley Center for Psychiatric Research at the Broad Institute for supporting control sample aggregation. M.A.R. is in part supported by the NHGRI of the NIH under award no. R01HG010140 and an NIH Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (no. 5U01HG009080). H.H. acknowledges support from NIDDK grant no. K01DK114379, grant no. P30DK043351 and the Stanley Center for Psychiatric Research. H.S.W. receives philanthropic support from Martin Schlaff, James Brooks and the B. Hasso Family Foundation. H.H.U. and A. Sazonovs. are supported by the NIHR Oxford Biomedical Research Centre and by The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is in part supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics grants no. 312074 and no. 336824. Individual studies contributing to this meta-analysis acknowledge support from NIH grants no. DK062431, no. DK062432, no. DK087694, no. K23DK117054, no. R01DK111843, no. P01DK094779, no. R01HG010140, no. 5U01HG009080 and no. DK062420, and NIDDK grants no. P01DK046763, no. U01DK062413 and no. R01DK104844. Funding Information: We thank all of the principal investigators, local staff from individual cohorts and all of the patients who kindly donated samples used in the study for making possible this global collaboration and resource to advance IBD genetics research. This research was funded in whole, or in part, by the US National Institutes of Health grants no. U54HG003067 and no. 5UM1HG008895, the Wellcome Trust grants no. 206194 and no. 108413/A/15/D, and The Leona M. \& Harry B. Helmsley Charitable Trust grant no. 2015PG-IBD001. We thank the Broad Institute Genomics Platform for genomic data generation efforts and the Stanley Center for Psychiatric Research at the Broad Institute for supporting control sample aggregation. M.A.R. is in part supported by the NHGRI of the NIH under award no. R01HG010140 and an NIH Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (no. 5U01HG009080). H.H. acknowledges support from NIDDK grant no. K01DK114379, grant no. P30DK043351 and the Stanley Center for Psychiatric Research. H.S.W. receives philanthropic support from Martin Schlaff, James Brooks and the B. Hasso Family Foundation. H.H.U. and A. Sazonovs. are supported by the NIHR Oxford Biomedical Research Centre and by The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is in part supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics grants no. 312074 and no. 336824. Individual studies contributing to this meta-analysis acknowledge support from NIH grants no. DK062431, no. DK062432, no. DK087694, no. K23DK117054, no. R01DK111843, no. P01DK094779, no. R01HG010140, no. 5U01HG009080 and no. DK062420, and NIDDK grants no. P01DK046763, no. U01DK062413 and no. R01DK104844. Funding Information: A. Baras., M. Ferreira., J.E.H. and D.S are current or former employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. M.A. is consulting for or part of the advisory board for AbbVie Inc., Bellatrix Pharmaceuticals, Bristol Myers Squibb, Eli Lilly Pharmaceuticals, Gilead, Janssen Ortho, LLC, and Prometheus Biosciences; and teaching, lecturing or speaking at Alimentiv, Arena Pharmaceuticals, Janssen, Prime CME, Takeda Pharmaceuticals. A.B. is an employee of Regeneron and owns stock in Regeneron. O.M.D. has served in the IBD fellowship funding committee for Pfizer and has a funded research project by Pfizer. H.K. receives grant funding from Takeda and Pfizer and has received consulting fees from Takeda. A.P. is a member of Astra Zenecas Genomics Advisory Board. M.A.R. is on the SAB of 54gene and has advised BioMarin, Third Rock Ventures, MazeTx and Related Sciences. G.A.H. is an employee of Takeda, former employee of AbbVie and owns stock in Takeda and AbbVie. C.A.L. reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma and grants from AstraZeneca, outside the submitted work. H.H.U. reports research collaboration or consultancy with Janssen, Eli Lilly, UCB Pharma, Celgene, MiroBio, OMass and Mestag. D.P.B.M. has consulted for Takeda, Boehringer Ingelheim, Palatin Technologies, Bridge Biotherapeutics, Pfizer and Gilead. M.P. received an unrestricted research grant from Pfizer UK and speaker fees from Janssen. P.I. received lecture fees from AbbVie, BMS, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire and Warner Chilcott; financial support for research from Celltrion, MSD, Pfizer and Takeda; advisory fees from AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma and Warner Chilcott. Cedars-Sinai and D.P.B.M. have financial interests in Prometheus Biosciences, a company which has access to the data and specimens in Cedars-Sinais MIRIAD Biobank (including the Cedars-Sinai data and specimens used in this study) and seeks to develop commercial products. H.H. has received consultancy fees from Ono Pharmaceutical and honoraria from Xian Janssen Pharmaceutical. C.A.A. has received consultancy fees from Genomics plc and BridgeBio Inc. and lecture fees from GSK. M.J.D. is a founder of Maze Therapeutics. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01156-2",

language = "English",

volume = "54",

pages = "1275--1283",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

TY - JOUR

T1 - Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

AU - Sazonovs, Aleksejs

AU - Stevens, Christine R

AU - Venkataraman, Guhan R

AU - Yuan, Kai

AU - Avila, Brandon

AU - Abreu, Maria T

AU - Ahmad, Tariq

AU - Allez, Matthieu

AU - Ananthakrishnan, Ashwin N

AU - Atzmon, Gil

AU - Baras, Aris

AU - Barrett, Jeffrey C

AU - Barzilai, Nir

AU - Beaugerie, Laurent

AU - Beecham, Ashley

AU - Bernstein, Charles N

AU - Bitton, Alain

AU - Bokemeyer, Bernd

AU - Chan, Andrew

AU - Chung, Daniel

AU - Cleynen, Isabelle

AU - Cosnes, Jacques

AU - Cutler, David J

AU - Daly, Allan

AU - Damas, Oriana M

AU - Datta, Lisa W

AU - Dawany, Noor

AU - Devoto, Marcella

AU - Dodge, Sheila

AU - Ellinghaus, Eva

AU - Fachal, Laura

AU - Farkkila, Martti

AU - Faubion, William

AU - Ferreira, Manuel

AU - Franchimont, Denis

AU - Gabriel, Stacey B

AU - Ge, Tian

AU - Georges, Michel

AU - Gettler, Kyle

AU - Giri, Mamta

AU - Glaser, Benjamin

AU - Goerg, Siegfried

AU - Goyette, Philippe

AU - Graham, Daniel

AU - Hämäläinen, Eija

AU - Haritunians, Talin

AU - Heap, Graham A

AU - Hiltunen, Mikko

AU - Irving, Peter

AU - Prescott, Natalie

AU - Belgium IBD Consortium

N1 - Funding Information: We thank all of the principal investigators, local staff from individual cohorts and all of the patients who kindly donated samples used in the study for making possible this global collaboration and resource to advance IBD genetics research. This research was funded in whole, or in part, by the US National Institutes of Health grants no. U54HG003067 and no. 5UM1HG008895, the Wellcome Trust grants no. 206194 and no. 108413/A/15/D, and The Leona M. & Harry B. Helmsley Charitable Trust grant no. 2015PG-IBD001. We thank the Broad Institute Genomics Platform for genomic data generation efforts and the Stanley Center for Psychiatric Research at the Broad Institute for supporting control sample aggregation. M.A.R. is in part supported by the NHGRI of the NIH under award no. R01HG010140 and an NIH Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (no. 5U01HG009080). H.H. acknowledges support from NIDDK grant no. K01DK114379, grant no. P30DK043351 and the Stanley Center for Psychiatric Research. H.S.W. receives philanthropic support from Martin Schlaff, James Brooks and the B. Hasso Family Foundation. H.H.U. and A. Sazonovs. are supported by the NIHR Oxford Biomedical Research Centre and by The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is in part supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics grants no. 312074 and no. 336824. Individual studies contributing to this meta-analysis acknowledge support from NIH grants no. DK062431, no. DK062432, no. DK087694, no. K23DK117054, no. R01DK111843, no. P01DK094779, no. R01HG010140, no. 5U01HG009080 and no. DK062420, and NIDDK grants no. P01DK046763, no. U01DK062413 and no. R01DK104844. Funding Information: We thank all of the principal investigators, local staff from individual cohorts and all of the patients who kindly donated samples used in the study for making possible this global collaboration and resource to advance IBD genetics research. This research was funded in whole, or in part, by the US National Institutes of Health grants no. U54HG003067 and no. 5UM1HG008895, the Wellcome Trust grants no. 206194 and no. 108413/A/15/D, and The Leona M. & Harry B. Helmsley Charitable Trust grant no. 2015PG-IBD001. We thank the Broad Institute Genomics Platform for genomic data generation efforts and the Stanley Center for Psychiatric Research at the Broad Institute for supporting control sample aggregation. M.A.R. is in part supported by the NHGRI of the NIH under award no. R01HG010140 and an NIH Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (no. 5U01HG009080). H.H. acknowledges support from NIDDK grant no. K01DK114379, grant no. P30DK043351 and the Stanley Center for Psychiatric Research. H.S.W. receives philanthropic support from Martin Schlaff, James Brooks and the B. Hasso Family Foundation. H.H.U. and A. Sazonovs. are supported by the NIHR Oxford Biomedical Research Centre and by The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is in part supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics grants no. 312074 and no. 336824. Individual studies contributing to this meta-analysis acknowledge support from NIH grants no. DK062431, no. DK062432, no. DK087694, no. K23DK117054, no. R01DK111843, no. P01DK094779, no. R01HG010140, no. 5U01HG009080 and no. DK062420, and NIDDK grants no. P01DK046763, no. U01DK062413 and no. R01DK104844. Funding Information: A. Baras., M. Ferreira., J.E.H. and D.S are current or former employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. M.A. is consulting for or part of the advisory board for AbbVie Inc., Bellatrix Pharmaceuticals, Bristol Myers Squibb, Eli Lilly Pharmaceuticals, Gilead, Janssen Ortho, LLC, and Prometheus Biosciences; and teaching, lecturing or speaking at Alimentiv, Arena Pharmaceuticals, Janssen, Prime CME, Takeda Pharmaceuticals. A.B. is an employee of Regeneron and owns stock in Regeneron. O.M.D. has served in the IBD fellowship funding committee for Pfizer and has a funded research project by Pfizer. H.K. receives grant funding from Takeda and Pfizer and has received consulting fees from Takeda. A.P. is a member of Astra Zenecas Genomics Advisory Board. M.A.R. is on the SAB of 54gene and has advised BioMarin, Third Rock Ventures, MazeTx and Related Sciences. G.A.H. is an employee of Takeda, former employee of AbbVie and owns stock in Takeda and AbbVie. C.A.L. reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma and grants from AstraZeneca, outside the submitted work. H.H.U. reports research collaboration or consultancy with Janssen, Eli Lilly, UCB Pharma, Celgene, MiroBio, OMass and Mestag. D.P.B.M. has consulted for Takeda, Boehringer Ingelheim, Palatin Technologies, Bridge Biotherapeutics, Pfizer and Gilead. M.P. received an unrestricted research grant from Pfizer UK and speaker fees from Janssen. P.I. received lecture fees from AbbVie, BMS, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire and Warner Chilcott; financial support for research from Celltrion, MSD, Pfizer and Takeda; advisory fees from AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma and Warner Chilcott. Cedars-Sinai and D.P.B.M. have financial interests in Prometheus Biosciences, a company which has access to the data and specimens in Cedars-Sinais MIRIAD Biobank (including the Cedars-Sinai data and specimens used in this study) and seeks to develop commercial products. H.H. has received consultancy fees from Ono Pharmaceutical and honoraria from Xian Janssen Pharmaceutical. C.A.A. has received consultancy fees from Genomics plc and BridgeBio Inc. and lecture fees from GSK. M.J.D. is a founder of Maze Therapeutics. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85137084709

U2 - 10.1038/s41588-022-01156-2

DO - 10.1038/s41588-022-01156-2

M3 - Article

C2 - 36038634

SN - 1061-4036

VL - 54

SP - 1275

EP - 1283

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

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

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