. 2022 Sep;54(9):1275-1283.

doi: 10.1038/s41588-022-01156-2. Epub 2022 Aug 29.

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

Aleksejs Sazonovs^#¹, Christine R Stevens^#^{2

3

4}, Guhan R Venkataraman^#⁵, Kai Yuan^#^{3

4}, Brandon Avila², Maria T Abreu⁶, Tariq Ahmad⁷, Matthieu Allez⁸, Ashwin N Ananthakrishnan⁹, Gil Atzmon^{10

11}, Aris Baras¹², Jeffrey C Barrett¹³, Nir Barzilai^{11

14}, Laurent Beaugerie¹⁵, Ashley Beecham^{16

17}, Charles N Bernstein¹⁸, Alain Bitton¹⁹, Bernd Bokemeyer²⁰, Andrew Chan^{21

22}, Daniel Chung²³, Isabelle Cleynen²⁴, Jacques Cosnes²⁵, David J Cutler^{26

27}, Allan Daly²⁸, Oriana M Damas²⁹, Lisa W Datta³⁰, Noor Dawany³¹, Marcella Devoto^{31

32

33

34}, Sheila Dodge³⁵, Eva Ellinghaus³⁶, Laura Fachal¹, Martti Farkkila³⁷, William Faubion³⁸, Manuel Ferreira¹², Denis Franchimont³⁹, Stacey B Gabriel³⁵, Tian Ge^{3

40

41}, Michel Georges⁴², Kyle Gettler⁴³, Mamta Giri⁴³, Benjamin Glaser⁴⁴, Siegfried Goerg⁴⁵, Philippe Goyette⁴⁶, Daniel Graham^{47

48

49}, Eija Hämäläinen⁵⁰, Talin Haritunians⁵¹, Graham A Heap⁷, Mikko Hiltunen⁵², Marc Hoeppner⁵³, Julie E Horowitz¹², Peter Irving^{54

55}, Vivek Iyer²⁸, Chaim Jalas⁵⁶, Judith Kelsen³¹, Hamed Khalili²¹, Barbara S Kirschner⁵⁷, Kimmo Kontula⁵⁸, Jukka T Koskela⁵⁰, Subra Kugathasan²⁷, Juozas Kupcinskas⁵⁹, Christopher A Lamb^{60

61}, Matthias Laudes⁴⁵, Chloé Lévesque⁴⁶, Adam P Levine⁶², James D Lewis^{34

63}, Claire Liefferinckx³⁹, Britt-Sabina Loescher³⁶, Edouard Louis⁴², John Mansfield^{60

61}, Sandra May³⁶, Jacob L McCauley^{16

17}, Emebet Mengesha⁵¹, Myriam Mni⁴², Paul Moayyedi⁶⁴, Christopher J Moran²³, Rodney D Newberry⁶⁵, Sirimon O'Charoen⁶³, David T Okou^{27

66}, Bas Oldenburg⁶⁷, Harry Ostrer⁶⁸, Aarno Palotie^{2

3

4

50

69

70}, Jean Paquette⁴⁶, Joel Pekow⁵⁷, Inga Peter⁴³, Marieke J Pierik⁷¹, Cyriel Y Ponsioen⁷², Nikolas Pontikos⁶², Natalie Prescott⁷³, Ann E Pulver⁷⁴, Souad Rahmouni⁴², Daniel L Rice¹, Päivi Saavalainen⁷⁵, Bruce Sands⁴³, R Balfour Sartor⁷⁶, Elena R Schiff⁶², Stefan Schreiber³⁶, L Philip Schumm⁷⁷, Anthony W Segal⁶², Philippe Seksik¹⁵, Rasha Shawky⁷⁸, Shehzad Z Sheikh⁷⁶, Mark S Silverberg⁷⁹, Alison Simmons⁸⁰, Jurgita Skeiceviciene⁵⁹, Harry Sokol¹⁵, Matthew Solomonson², Hari Somineni⁸¹, Dylan Sun¹², Stephan Targan⁵¹, Dan Turner⁸², Holm H Uhlig^{83

84}, Andrea E van der Meulen⁸⁵, Séverine Vermeire^{86

87}, Sare Verstockt⁸⁷, Michiel D Voskuil⁸⁸, Harland S Winter²³, Justine Young⁶³; Belgium IBD Consortium; Cedars-Sinai IBD; International IBD Genetics Consortium; NIDDK IBD Genetics Consortium; NIHR IBD BioResource; Regeneron Genetics Center; SHARE Consortium; SPARC IBD Network; UK IBD Genetics Consortium; Richard H Duerr⁸⁹, Andre Franke³⁶, Steven R Brant^{30

90}, Judy Cho⁴³, Rinse K Weersma⁸⁸, Miles Parkes⁹¹, Ramnik J Xavier^{47

48

49

92

93

94

95

96}, Manuel A Rivas⁵, John D Rioux^{46

97}, Dermot P B McGovern⁵¹, Hailiang Huang^{98

99}, Carl A Anderson¹⁰⁰, Mark J Daly^{101

102

103

104}

Affiliations

¹ Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
² Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
⁶ Crohn's and Colitis Center, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
⁷ Royal Devon and Exeter Hospital, Exeter, UK.
⁸ Hopital Saint-Louis, APHP, Universite de Paris, INSERM U1160, Paris, France.
⁹ Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department for Human Biology, University of Haifa, Haifa, Israel.
¹¹ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
¹² Regeneron Genetics Center, Tarrytown, NY, USA.
¹³ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹⁴ The Institute for Aging Research, The Nathan Shock Center of Excellence in the Basic Biology of Aging and the Paul F. Glenn Center for the Biology of Human Aging Research at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.
¹⁵ Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France.
¹⁶ John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
¹⁷ The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
¹⁸ University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁹ McGill University and McGill University Health Centre, Montreal, Quebec, Canada.
²⁰ Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
²¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
²² Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA.
²³ Massachusetts General Hospital, Boston, MA, USA.
²⁴ Department of Human Genetics, KU Leuven, Leuven, Belgium.
²⁵ Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France.
²⁶ Department of Human Genetics, Emory University, Atlanta, GA, USA.
²⁷ Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
²⁸ Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
²⁹ University of Miami, Miami, FL, USA.
³⁰ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³¹ Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
³² University of Rome Sapienza, Rome, Italy.
³³ IRGB - CNR, Cagliari, Italy.
³⁴ Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
³⁵ Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁶ Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
³⁷ Helsinki University Central Hospital, Helsinki, Finland.
³⁸ Mayo Clinic, Rochester, Rochester, MN, USA.
³⁹ Erasme Hospital, ULB, Brussels, Belgium.
⁴⁰ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴¹ Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁴² University of Liège, ULG, Liège, Belgium.
⁴³ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁴ Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
⁴⁵ University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴⁶ Research Center Montreal Heart Institute, Montreal, Quebec, Canada.
⁴⁷ Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴⁸ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
⁴⁹ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
⁵⁰ Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
⁵¹ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
⁵² Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
⁵³ Christian-Albrechts-University of Kiel, Kiel, Germany.
⁵⁴ Department of Gastroenterology, Guys and Saint Thomas Hospital, London, UK.
⁵⁵ School of Immunology and Microbial Sciences, Kings College London, London, UK.
⁵⁶ Director of Genetic Resources and Services, Center for Rare Jewish Genetic Disorders, Bonei Olam, Brooklyn, NY, USA.
⁵⁷ Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA.
⁵⁸ Department of Medicine, Helsinki University Hospital, and Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
⁵⁹ Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁶⁰ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁶¹ Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶² University College London, London, UK.
⁶³ Crohn's and Colitis Foundation, New York, NY, USA.
⁶⁴ McMaster University, Hamilton, Ontario, Canada.
⁶⁵ Washington University School of Medicine, St. Louis, MO, USA.
⁶⁶ Institut National de Sante Publique (INSP), Abidjan, Côte d'Ivoire.
⁶⁷ Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁶⁸ Albert Einstein College of Medicine, Bronx, NY, USA.
⁶⁹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁷⁰ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁷¹ Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁷² Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
⁷³ Department of Medical and Molecular Genetics, Kings College London, London, UK.
⁷⁴ School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷⁵ Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.
⁷⁶ Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁷⁷ Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
⁷⁸ IBD BioResource, NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁷⁹ Mount Sinai Hospital, Toronto, Ontario, Canada.
⁸⁰ MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁸¹ Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁸² Shaare Zedek Medical Center, Jerusalem, Israel.
⁸³ Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
⁸⁴ Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
⁸⁵ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁸⁶ University Hospitals Leuven, Leuven, Belgium.
⁸⁷ Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
⁸⁸ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
⁸⁹ University of Pittsburgh, Pittsburgh, PA, USA.
⁹⁰ Crohn's Colitis Center of New Jersey, Department of Medicine, Rutgers Robert Wood Johnson Medical School and Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, New Brunswick and Piscataway, NJ, USA.
⁹¹ Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁹² Kurt Isselbacher Professor of Medicine at Harvard Medical School, Cambridge, MA, USA.
⁹³ Core Institute Member, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁴ Klarman Cell Observatory, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁵ Immunology Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁶ Center for Microbiome Informatics and Therapeutics at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹⁷ Faculty of Medicine, Université de Montréal, Montreal, Canada.
⁹⁸ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. hhuang@broadinstitute.org.
⁹⁹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. hhuang@broadinstitute.org.
¹⁰⁰ Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. carl.anderson@sanger.ac.uk.
¹⁰¹ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@broadinstitute.org.
¹⁰² Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@broadinstitute.org.
¹⁰³ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@broadinstitute.org.
¹⁰⁴ Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland. mjdaly@broadinstitute.org.

^# Contributed equally.

PMID: 36038634
PMCID: PMC9700438
DOI: 10.1038/s41588-022-01156-2

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

Aleksejs Sazonovs et al. Nat Genet. 2022 Sep.

. 2022 Sep;54(9):1275-1283.

doi: 10.1038/s41588-022-01156-2. Epub 2022 Aug 29.

Authors

Affiliations

¹ Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
² Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
⁶ Crohn's and Colitis Center, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
⁷ Royal Devon and Exeter Hospital, Exeter, UK.
⁸ Hopital Saint-Louis, APHP, Universite de Paris, INSERM U1160, Paris, France.
⁹ Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department for Human Biology, University of Haifa, Haifa, Israel.
¹¹ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
¹² Regeneron Genetics Center, Tarrytown, NY, USA.
¹³ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹⁴ The Institute for Aging Research, The Nathan Shock Center of Excellence in the Basic Biology of Aging and the Paul F. Glenn Center for the Biology of Human Aging Research at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.
¹⁵ Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France.
¹⁶ John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
¹⁷ The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
¹⁸ University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁹ McGill University and McGill University Health Centre, Montreal, Quebec, Canada.
²⁰ Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
²¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
²² Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA.
²³ Massachusetts General Hospital, Boston, MA, USA.
²⁴ Department of Human Genetics, KU Leuven, Leuven, Belgium.
²⁵ Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France.
²⁶ Department of Human Genetics, Emory University, Atlanta, GA, USA.
²⁷ Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
²⁸ Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
²⁹ University of Miami, Miami, FL, USA.
³⁰ Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³¹ Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
³² University of Rome Sapienza, Rome, Italy.
³³ IRGB - CNR, Cagliari, Italy.
³⁴ Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
³⁵ Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁶ Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
³⁷ Helsinki University Central Hospital, Helsinki, Finland.
³⁸ Mayo Clinic, Rochester, Rochester, MN, USA.
³⁹ Erasme Hospital, ULB, Brussels, Belgium.
⁴⁰ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴¹ Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁴² University of Liège, ULG, Liège, Belgium.
⁴³ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁴ Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
⁴⁵ University Medical Center Schleswig-Holstein, Kiel, Germany.
⁴⁶ Research Center Montreal Heart Institute, Montreal, Quebec, Canada.
⁴⁷ Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴⁸ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
⁴⁹ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
⁵⁰ Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
⁵¹ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
⁵² Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
⁵³ Christian-Albrechts-University of Kiel, Kiel, Germany.
⁵⁴ Department of Gastroenterology, Guys and Saint Thomas Hospital, London, UK.
⁵⁵ School of Immunology and Microbial Sciences, Kings College London, London, UK.
⁵⁶ Director of Genetic Resources and Services, Center for Rare Jewish Genetic Disorders, Bonei Olam, Brooklyn, NY, USA.
⁵⁷ Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA.
⁵⁸ Department of Medicine, Helsinki University Hospital, and Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
⁵⁹ Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁶⁰ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁶¹ Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶² University College London, London, UK.
⁶³ Crohn's and Colitis Foundation, New York, NY, USA.
⁶⁴ McMaster University, Hamilton, Ontario, Canada.
⁶⁵ Washington University School of Medicine, St. Louis, MO, USA.
⁶⁶ Institut National de Sante Publique (INSP), Abidjan, Côte d'Ivoire.
⁶⁷ Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁶⁸ Albert Einstein College of Medicine, Bronx, NY, USA.
⁶⁹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁷⁰ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁷¹ Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁷² Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
⁷³ Department of Medical and Molecular Genetics, Kings College London, London, UK.
⁷⁴ School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷⁵ Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.
⁷⁶ Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁷⁷ Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
⁷⁸ IBD BioResource, NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁷⁹ Mount Sinai Hospital, Toronto, Ontario, Canada.
⁸⁰ MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁸¹ Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁸² Shaare Zedek Medical Center, Jerusalem, Israel.
⁸³ Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
⁸⁴ Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
⁸⁵ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁸⁶ University Hospitals Leuven, Leuven, Belgium.
⁸⁷ Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
⁸⁸ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
⁸⁹ University of Pittsburgh, Pittsburgh, PA, USA.
⁹⁰ Crohn's Colitis Center of New Jersey, Department of Medicine, Rutgers Robert Wood Johnson Medical School and Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, New Brunswick and Piscataway, NJ, USA.
⁹¹ Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁹² Kurt Isselbacher Professor of Medicine at Harvard Medical School, Cambridge, MA, USA.
⁹³ Core Institute Member, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁴ Klarman Cell Observatory, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁵ Immunology Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁶ Center for Microbiome Informatics and Therapeutics at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹⁷ Faculty of Medicine, Université de Montréal, Montreal, Canada.
⁹⁸ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. hhuang@broadinstitute.org.
⁹⁹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. hhuang@broadinstitute.org.
¹⁰⁰ Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. carl.anderson@sanger.ac.uk.
¹⁰¹ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@broadinstitute.org.
¹⁰² Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@broadinstitute.org.
¹⁰³ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@broadinstitute.org.
¹⁰⁴ Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland. mjdaly@broadinstitute.org.

^# Contributed equally.

PMID: 36038634
PMCID: PMC9700438
DOI: 10.1038/s41588-022-01156-2

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.

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Conflict of interest statement

Competing Interests Statement

A.B., M.F, J.E.H., 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; 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, 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 honorarium 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.

Figures

**Extended Data Fig. 1. Overview of the study design**
We utilized a logistic mixed-model for the association analysis, followed by the fixed-effect meta-analysis to combine multiple cohorts. Multiple cohorts serve the purpose of replication. Two large cohorts at Broad Institute of different exome capture platforms were used to discover candidate variants (Nextera WES and Twist WES ). Two independent cohorts at Sanger (Sanger WGS and Sanger WES) and one Kiel/Regeneron cohort (Regeneron WES) were used to replicate the findings.

**Extended Data Fig. 2. Quality control procedures applied in the Broad sequencing pipeline**
We show as an example the quality control steps performed on variants and subjects from the Broad sequencing platform. Quality controls performed on data from other platforms follow a similar plan and are described in Methods. Quality control steps using external information from gnomAD were colored green. Thresholds and details can be found in Methods.

**Extended Data Fig. 3. QQ plots of the heterogeneity-of-effect test between the Nextera and Twist discovery cohorts**
Only QC passed variants with minor allele frequency in NFE between 0.0001 and 0.10 were included. a, all variants. b, non-synonymous variants. c, synonymous variants. In a and b, the y axis is capped at -log₁₀ p = 30 while the top four variants (three in *NOD2* and one in *IL23R*) have -log₁₀ p > 100. In c, to remove the synonymous variants that tag causal non-synonymous variants and artifacts through LD, we removed loci hosting large-effect coding variants (*IL23R*, *NOD2*, *LRRK2*, *TYK2*, *ATG16L1*, *SLC39A8*, *PTGER4*, *IRGM*, *CARD9*), implicated by variants removed in the heterogeneous test (*AHNAK2, LILRA*), and with long range LD (MHC).

**Extended Data Fig. 4. Power to detect single variant associations.**
We performed a series of power calculations using the methodology described by Johnson and Abecasis (2017). Our initial ‘exome-wide scan’ (two cohorts) had fewer samples and a more lenient significance threshold than subsequent meta-analysis (five cohorts). However, both analyses had similar power to detect true associations at their respective significance levels. Our single-variant association analyses did not have the power to uncover association to variants with a MAF = 0.0001 and below (unless the variant has a very strong effect, e.g. 0.76 power at OR = 8). Similarly, the exome-wide scan had limited power to detect association to variants with a MAF = 0.001 and OR < 2, but was well-powered above these thresholds. a, Power of the exome-wide scan analysis b, Power of the meta-analysis. c, Power to detect single-variant associations at different minor allele frequencies at α = 0.0002 (‘scan’; dashed lines) and 3 x 10–7 (‘meta’; solid lines) and assuming Crohn’s disease population prevalence of 276 in 100,000, and an additive effect model.

**Extended Data Fig. 5. Relation to known IBD associations**
Numbers in brackets are the number of variants assigned to the categories out of the 45 exome-wide significant variants.

**Extended Data Fig. 6. WES variants from this study implicating known IBD loci**
**a-c:** a novel CD variant implicating *TAGAP*. **d-g:** CD variants tagging fine-mapped IBD associations in *LRRK2*. a and d, P-value for variants from the fine-mapping study5. b and e, PIP from fine-mapping. c, f and g, P-value for variants from this study. Open circle indicating LD information is missing. LD calculated between the plotted variant and the best variant in b for panel c, and variants with best PIP in credible sets 1 and 2 (panel e) respectively for panels f and g.

**Extended Data Fig. 7. Nextera and Twist callset population assignment.**
Principal components for **a, c,** before removing non-European samples for Twist and Nextera respectively. **b, d,** after removing non-European samples for Twist and Nextera respectively. Principal components generated from the 1000 Genome Project Phase III data and different colors stand for different continental / superpopulations. Study subjects (black dots) were projected onto principal components.

**Figure 1.. Odds ratio and minor allele frequency for exome-wide significant findings that are not tagging stronger, established non-coding association signals.**
*Known causal candidate:* in a credible set from a fine-mapping study with posterior inclusion probability > 5% or reported in previous studies^, (Online Methods). *New locus:* in a locus not yet implicated by GWAS. *New variant in known locus:* in a known GWAS locus, but represents an association independent from previously-reported IBD putative causal variants (Online Methods).

**Figure 2.. Schematic representation of inflamed mucosa showing the mesenchymal related genes with newly identified mutations.**
(1) Following mucosal injury, mesenchymal cells (MCs) are highly activated by pro-inflammatory signals such as TNF-α, CCL19/CCL21, PAF and TGF-β1. (2) Among these, TNF-α increases PAF-R expression in intestinal epithelial cells during wound repair. However, prolonged exposure to PAF dissolves cell junctions and increases epithelial permeability. In endothelial cells, the PAF-R/PAF axis has a similar effect on Vascular Endothelial-Cadherin (VE-CAD) assembly. A leaky endothelium can result in an increase in immune cell infiltration and aggravate inflammation at injured sites. (3) Secretion of CCL19/CCL21 by activated stromal fibroblasts in response to epithelial damage or infection attracts dendritic cells (DC) and other immune cells which then migrate to mesenteric lymph nodes, where the immune response is coordinated. CCR7+ DC, macrophages and T cells also exacerbate inflammation through pro-inflammatory mediators such as CCL19/CCL21. Plasma cells express SDF2L1 in response to inflammation and ER stress due to massive antibody production. (4) Mucosal repair mediated by TGF-β1/SMAD3 signaling has a key role in epithelial homeostasis after tissue injury. Importantly, a causal variant in SMAD3* further supports the importance of this pathway in disease susceptibility. PDLIM5 is a known regulator of *SMAD3* stability during EMT. Uncontrolled EMT increases fibroblast proliferation and excessive ECM production leading to fibrosis. Active HGF released by HGFAC antagonizes TGF-β1 resulting in a decrease of EMT. (5) HGF secreted by fibroblasts play a role in maintaining the stem cell niche in intestinal crypts. SDF2L1 expressed by Paneth cells in response to ER stress may participate in this process. (6) The current genetic findings provide support to the scientific rationale for targeting EMT and fibrosis for the treatment of CD, such as with anti-integrin antibodies (anti-αvβ6), recombinant human HGF (rhHGF) and Rho Kinase Inhibitor (ROCKi); shown in red.

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References

1. Jostins L et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012). - PMC - PubMed
1. Liu JZ et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015). - PMC - PubMed
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Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

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

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