Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Chris Eijsbouts; Tenghao Zheng; Nicholas A Kennedy; Ferdinando Bonfiglio; Carl A Anderson; Loukas Moutsianas; Joanne Holliday; Jingchunzi Shi; Suyash Shringarpure; 23andMe Research Team; Alexandru-Ioan Voda; Bellygenes Initiative; Gianrico Farrugia; Andre Franke; Matthias Hübenthal; Gonçalo Abecasis; Matthew Zawistowski; Anne Heidi Skogholt; Eivind Ness-Jensen; Kristian Hveem; Tõnu Esko; Maris Teder-Laving; Alexandra Zhernakova; Michael Camilleri; Guy Boeckxstaens; Peter J Whorwell; Robin Spiller; Gil McVean; Mauro D'Amato; Luke Jostins; Miles Parkes

doi:10.1038/s41588-021-00950-8

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Nat Genet. 2021 Nov;53(11):1543-1552. doi: 10.1038/s41588-021-00950-8. Epub 2021 Nov 5.

Authors

Chris Eijsbouts^{1

2}, Tenghao Zheng^#^{3

4}, Nicholas A Kennedy^#⁵, Ferdinando Bonfiglio^{3

4}, Carl A Anderson⁶, Loukas Moutsianas^{6

7}, Joanne Holliday⁸, Jingchunzi Shi⁹, Suyash Shringarpure⁹; 23andMe Research Team; Alexandru-Ioan Voda^{10

11}; Bellygenes Initiative; Gianrico Farrugia¹², Andre Franke¹³, Matthias Hübenthal^{13

14}, Gonçalo Abecasis¹⁵, Matthew Zawistowski¹⁵, Anne Heidi Skogholt^{16

17}, Eivind Ness-Jensen^{17

18

19}, Kristian Hveem¹⁷, Tõnu Esko²⁰, Maris Teder-Laving²⁰, Alexandra Zhernakova²¹, Michael Camilleri²², Guy Boeckxstaens²³, Peter J Whorwell²⁴, Robin Spiller²⁵, Gil McVean¹, Mauro D'Amato^{26

27

28

29

30

31}, Luke Jostins^{32

33

34}, Miles Parkes^{35

36}

Collaborators

Michelle Agee, Stella Aslibekyan, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah K Clark, Sarah L Elson, Kipper Fletez-Brant, Pierre Fontanillas, Nicholas A Furlotte, Pooja M Gandhi, Karl Heilbron, Barry Hicks, David A Hinds, Karen E Huber, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Marie K Luff, Jey C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Sahar V Mozaffari, Priyanka Nandakumar, Elizabeth S Noblin, Carrie A M Northover, Jared O'Connell, Aaron A Petrakovitz, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Anjali J Shastri, Janie F Shelton, Chao Tian, Joyce Y Tung, Robert J Tunney, Vladimir Vacic, Xin Wang, Amir S Zare, Purna Kashyap, Lin Chang, Emeran Mayer, Margaret Heitkemper, Gregory S Sayuk, Tamar Ringel-Kulka, Yehuda Ringel, William D Chey, Shanti Eswaran, Juanita L Merchant, Robert J Shulman, Luis Bujanda, Koldo Garcia-Etxebarria, Aldona Dlugosz, Greger Lindberg, Peter T Schmidt, Pontus Karling, Bodil Ohlsson, Susanna Walter, Åshild O Faresjö, Magnus Simren, Jonas Halfvarson, Piero Portincasa, Giovanni Barbara, Paolo Usai-Satta, Matteo Neri, Gerardo Nardone, Rosario Cuomo, Francesca Galeazzi, Massimo Bellini, Anna Latiano, Lesley Houghton, Daisy Jonkers, Alexander Kurilshikov, Rinse K Weersma, Mihai Netea, Jonas Tesarz, Annika Gauss, Miriam Goebel-Stengel, Viola Andresen, Thomas Frieling, Christian Pehl, Rainer Schaefert, Beate Niesler, Wolfgang Lieb, Kurt Hanevik, Nina Langeland, Knut-Arne Wensaas, Sverre Litleskare, Maiken E Gabrielsen, Laurent Thomas, Vincent Thijs, Robin Lemmens, Lukas Van Oudenhove, Mira Wouters

Affiliations

¹ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
² Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
³ Center for Molecular Medicine & Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
⁴ School of Biological Sciences, Monash University, Clayton, Victoria, Australia.
⁵ IBD Pharmacogenetics, College of Medicine and Health, University of Exeter, Exeter, UK.
⁶ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
⁷ William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
⁸ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁹ 23andMe, Inc., Sunnyvale, CA, USA.
¹⁰ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
¹¹ Saint Edmund Hall, University of Oxford, Oxford, UK.
¹² Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
¹³ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
¹⁴ Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁵ Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA.
¹⁶ Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁷ Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁸ Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
¹⁹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
²⁰ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
²¹ Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
²² Clinical Enteric Neuroscience Translational and Epidemiological Research and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
²³ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
²⁴ Neurogastroenterology Unit, Wythenshawe Hospital, Centre for Gastrointestinal Sciences, University of Manchester, Manchester, UK.
²⁵ Nottingham Digestive Diseases Centre, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
²⁶ Center for Molecular Medicine & Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. [email protected].
²⁷ School of Biological Sciences, Monash University, Clayton, Victoria, Australia. [email protected].
²⁸ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. [email protected].
²⁹ Biodonostia Health Research Institute, San Sebastian, Spain. [email protected].
³⁰ Gastrointestinal Genetics Lab, CIC bioGUNE - Basque Research and Technology Alliance, Derio, Spain. [email protected].
³¹ IKERBASQUE, The Basque Science Foundation, Bilbao, Spain. [email protected].
³² Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. [email protected].
³³ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. [email protected].
³⁴ Christ Church, University of Oxford, Oxford, UK. [email protected].
³⁵ Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK. [email protected].
³⁶ Department of Gastroenterology, Cambridge University Hospital, Cambridge, UK. [email protected].

^# Contributed equally.

Abstract

Irritable bowel syndrome (IBS) results from disordered brain-gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (r_g > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain-gut interactions underlying IBS.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Anxiety Disorders / genetics*
CD56 Antigen / genetics
Cell Adhesion Molecules / genetics
Cytoskeletal Proteins / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Guanine Nucleotide Exchange Factors / genetics
Homeodomain Proteins / genetics
Humans
Irritable Bowel Syndrome / epidemiology
Irritable Bowel Syndrome / genetics*
Male
Middle Aged
Molecular Chaperones / genetics
Mood Disorders / genetics*
Polymorphism, Single Nucleotide
United Kingdom / epidemiology

Substances

BAG6 protein, human
CADM2 protein, human
CD56 Antigen
CKAP2 protein, human
Cell Adhesion Molecules
Cytoskeletal Proteins
DOCK9 protein, human
Guanine Nucleotide Exchange Factors
Homeodomain Proteins
Molecular Chaperones
NCAM1 protein, human
PHF2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding