{
  "abstract": "Background Idiopathic achalasia (IA) is characterised by the degeneration of neurons in the myenteric plexus leading to an irreversible impaired oesophageal function. Although immune-mediated mechanisms have been proposed, the underlying aetiopathology of IA remains poorly understood.Objective This study aimed to uncover the genetic risk architecture of IA.Design We carried out the first genome-wide association study (GWAS) on 4602 European patients with IA and 10 766 ethnically-matched controls.Results A single nucleotide polymorphism (SNP) in HLA-DQB1 leading to an 8-amino acid insertion on the protein level conferred strongest IA risk (PQGPPPAG: p=3.27×10–68, OR=2.45). Conditional analyses within the HLA locus revealed a complex genetic risk architecture. Three additional amino acid positions showed independent IA association (Omnibus p<5×10−8). These refer to positions 41 and 130 in HLA-DQα1, position 45 in HLA-DQβ1 and position 86 in HLA-DRβ1. Together, these findings highlight the pivotal role of class II HLA genetic variation in IA pathogenesis. Outside HLA, three independent variants showed IA association (p<5×10−8). One leads to an amino acid substitution with functional effect in PTPN22. Another risk variant leads to a downregulated expression of TNFSF8, TNFSF15 and TNC in immune cells. The third risk SNP is located near ZNF365, but the exact underlying cellular mechanism remains unknown. Beyond the single marker level, polygenic risk scores revealed that patients with IA can be stratified based on their genetic risk. In addition, IA shows a shared aetiopathology with Crohn’s disease (rg=0.335). Integrating GWAS and single-cell RNA-sequencing data from the myenteric plexus showed that the memory T-cell type FOS+Tc4+CD8+ plays a central role in IA development (p=2.50×10−19).Conclusion This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology.",
  "authors": [
    {
      "affiliations": [
        "Institute of Human Genetics, University of Marburg, Marburg, Germany"
      ],
      "name": "Sandeep Grover"
    },
    {
      "affiliations": [
        "Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany"
      ],
      "name": "Ines Gockel"
    },
    {
      "affiliations": [
        "Fondazione IRCCS Casa Sollievo della Sofferenza, Gastroenterology Unit, San Giovanni Rotondo, Foggia, Italy"
      ],
      "name": "Anna Latiano"
    },
    {
      "affiliations": [
        "Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland"
      ],
      "name": "Anna Mokrowiecka"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University of Marburg, Marburg, Germany"
      ],
      "name": "Pouria Dasmeh"
    },
    {
      "affiliations": [
        "Laboratory for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders, KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium"
      ],
      "name": "Mira M Wouters"
    },
    {
      "affiliations": [
        "Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic"
      ],
      "name": "Zuzana Vackova"
    },
    {
      "affiliations": [
        "Centre for Digestive Health, Department of Gastroenterology and Rheumatology, and Karolinska Institutet, Department of Medicine, Huddinge, Stockholm, Sweden"
      ],
      "name": "Stephan L Haas"
    },
    {
      "affiliations": [
        "Foregut Surgery Department, Hippokration General Hospital of Athens, Athens, Greece"
      ],
      "name": "Tania Triantafyllou"
    },
    {
      "affiliations": [
        "Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany"
      ],
      "name": "Nicole Kreuser"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University Hospital Bonn, Bonn, Germany"
      ],
      "name": "Jessica Trautmann"
    },
    {
      "affiliations": [
        "Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany"
      ],
      "name": "Stefan Niebisch"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University of Marburg, Marburg, Germany"
      ],
      "name": "Timo Hess"
    },
    {
      "affiliations": [
        "Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany"
      ],
      "name": "Rene Thieme"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University of Marburg, Marburg, Germany"
      ],
      "name": "Jessica Bigge"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium"
      ],
      "name": "Hubert Louis"
    },
    {
      "affiliations": [
        "Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium"
      ],
      "name": "Eric Quertinmont"
    },
    {
      "affiliations": [
        "Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France"
      ],
      "name": "Aline Meirhaeghe"
    },
    {
      "affiliations": [
        "Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France"
      ],
      "name": "Manon Muntaner"
    },
    {
      "affiliations": [
        "Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France"
      ],
      "name": "Philippe Amouyel"
    },
    {
      "affiliations": [
        "Univ Rouen Normandie, INSERM, Normandie Univ, ADEN UMR1073, CHU Rouen, CIC-CRB 1404, Digestive Physiology Department, F-76000, Rouen, France"
      ],
      "name": "Guillaume Gourcerol"
    },
    {
      "affiliations": [
        "CHU Nantes, Institut des Maladies de l’Appareil Digestif, Nantes, France"
      ],
      "name": "Stanislas Bruley des Varannes"
    },
    {
      "affiliations": [
        "Digestive Physiology, Hospices Civils de Lyon, Hopital E Herriot, F-69437, Lyon, France",
        "Digestive Physiology, Lyon I University, F-69008, Lyon, France",
        "LabTAU, INSERM, Université Lyon 1, Univ Lyon, F-69003, Lyon, France"
      ],
      "name": "Francois Mion"
    },
    {
      "affiliations": [
        "Institute for Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany"
      ],
      "name": "Michael Vieth"
    },
    {
      "affiliations": [
        "1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Athens, Greece",
        "Department of Neurology, Columbia University, New York, New York, USA"
      ],
      "name": "Nikolaos Scarmeas"
    },
    {
      "affiliations": [
        "Fondazione IRCCS Casa Sollievo della Sofferenza, Gastroenterology Unit, San Giovanni Rotondo, Foggia, Italy"
      ],
      "name": "Orazio Palmieri"
    },
    {
      "affiliations": [
        "Fondazione IRCCS Casa Sollievo della Sofferenza, Gastroenterology Unit, San Giovanni Rotondo, Foggia, Italy"
      ],
      "name": "Francesca Tavano"
    },
    {
      "affiliations": [
        "Department of Translational Medicine, University of Ferrara, Ferrara, Italy"
      ],
      "name": "Roberto De Giorgio"
    },
    {
      "affiliations": [
        "Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milano, Italy",
        "Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy"
      ],
      "name": "Daniela Galimberti"
    },
    {
      "affiliations": [
        "Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy"
      ],
      "name": "Andrea Arighi"
    },
    {
      "affiliations": [
        "Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy",
        "Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"
      ],
      "name": "Beatrice Arosio"
    },
    {
      "affiliations": [
        "Erasmus MC Cancer Institute, Department of Gastroenterology & Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands"
      ],
      "name": "Marco Bruno"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland"
      ],
      "name": "Justyna Wasielica-Berger"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland"
      ],
      "name": "Magdalena Gawron-Kiszka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Medical University of Gdansk, Gdansk, Poland"
      ],
      "name": "Maria Janiak"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Medical University of Gdansk, Gdansk, Poland"
      ],
      "name": "Magdalena Siepsiak"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Medical University of Gdansk, Gdansk, Poland"
      ],
      "name": "Krystian Adrych"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland"
      ],
      "name": "Tomasz Marek"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland"
      ],
      "name": "Andrzej Dabrowski"
    },
    {
      "affiliations": [
        "Department of Plastic and Reconstructive Surgery, Medical University of Lublin, Lublin, Poland"
      ],
      "name": "Marek Majewski"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Internal Medicine, Military Institute of Medicine, Warsaw, Poland"
      ],
      "name": "Piotr Gietka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Internal Medicine, Military Institute of Medicine, Warsaw, Poland"
      ],
      "name": "Maciej Gonciarz"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain"
      ],
      "name": "Julio Pérez de la Serna"
    },
    {
      "affiliations": [
        "Servicio de Aparato Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, Badalona, Spain"
      ],
      "name": "Laisy Zacarías Martínez"
    },
    {
      "affiliations": [
        "Department of Public Health and Caring Sciences, Clinical Geriatrics, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Vilmantas Giedraitis"
    },
    {
      "affiliations": [
        "Department of Public Health and Caring Sciences, Clinical Geriatrics, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Lena Kilander"
    },
    {
      "affiliations": [
        "Karolinska Institutet, Department NVS, Division of aging research center, Center for Alzheimer Research, Solna, Sweden"
      ],
      "name": "Laura Fratiglioni"
    },
    {
      "affiliations": [
        "Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain",
        "Departamento de Bioquímica Médica, Biología Molecular e Inmunología. Universidad de Sevilla, Sevilla, Spain",
        "Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain"
      ],
      "name": "Luis Miguel Real"
    },
    {
      "affiliations": [
        "Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic"
      ],
      "name": "Julius Spicak"
    },
    {
      "affiliations": [
        "Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium",
        "Gastroenterology Division, University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Jan Tack"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University Hospital Bonn, Bonn, Germany",
        "NGS Core Facility, Medical Faculty, University of Bonn, Bonn, Germany"
      ],
      "name": "Stefanie Heilmann-Heimbach"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University Hospital Bonn, Bonn, Germany"
      ],
      "name": "Markus Nöthen"
    },
    {
      "affiliations": [
        "Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden",
        "Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada",
        "Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Martin Ingelsson"
    },
    {
      "affiliations": [
        "Karolinska Institutet, Department NVS, Division of Neurogeriatrics, Center for Alzheimer Research, Bioclinicum, Solna, Sweden",
        "Theme inflammation and Aging, Unit for hereditary Dementia, Karolinska University Hospital, Solna, Sweden"
      ],
      "name": "Caroline Graff"
    },
    {
      "affiliations": [
        "Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA",
        "Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Barcelona, Spain",
        "Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain"
      ],
      "name": "Agustín Ruiz"
    },
    {
      "affiliations": [
        "Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France"
      ],
      "name": "Jean-Charles Lambert"
    },
    {
      "affiliations": [
        "Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany",
        "Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, Bonn, Germany",
        "German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany",
        "Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany",
        "Department of Psychiatry & Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, Texas, USA"
      ],
      "name": "Alfredo Ramirez"
    },
    {
      "affiliations": [
        "Gastro-Praxis Wiesbaden, Wiesbaden, Germany"
      ],
      "name": "Alexander J Eckardt"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Endocrinology and Infectious Diseases, Philipps-University Marburg and University Hospital Marburg, Marburg, Germany"
      ],
      "name": "Michaela Müller"
    },
    {
      "affiliations": [
        "Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany"
      ],
      "name": "Michael Knapp"
    },
    {
      "affiliations": [
        "Center for Inner Medicine II, Klinikum Chemnitz gGmbH, Chemnitz, Germany"
      ],
      "name": "Thaddäus T Wissinowski"
    },
    {
      "affiliations": [
        "Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Germany"
      ],
      "name": "Jutta Keller"
    },
    {
      "affiliations": [
        "Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany"
      ],
      "name": "Christiane Josephine Bruns"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, University Hospital Essen, Essen, Germany"
      ],
      "name": "Christian Gerges"
    },
    {
      "affiliations": [
        "Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Duesseldorf, Germany"
      ],
      "name": "Horst Neuhaus"
    },
    {
      "affiliations": [
        "Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany"
      ],
      "name": "Thomas Rösch"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Infectious Diseases and Rheumatology, Charite - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany"
      ],
      "name": "Britta Siegmund"
    },
    {
      "affiliations": [
        "Department of Internal Medicine and Gastroenterology, Elisabeth-Krankenhaus-Essen, Essen, Germany"
      ],
      "name": "Brigitte Schumacher"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University Hospital, Magdeburg, Germany"
      ],
      "name": "Marino Venerito"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain"
      ],
      "name": "Antonio Ruiz de León"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy"
      ],
      "name": "Riccardo Rosati"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy"
      ],
      "name": "Vito Annese"
    },
    {
      "affiliations": [
        "Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy"
      ],
      "name": "Uberto Fumagalli"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy"
      ],
      "name": "Luigi Laghi"
    },
    {
      "affiliations": [
        "Lab-Genetics and molecular basis of complex diseases, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain"
      ],
      "name": "Elena Urcelay"
    },
    {
      "affiliations": [
        "CHU Nantes, Institut des Maladies de l’Appareil Digestif, Nantes, France"
      ],
      "name": "Fabienne Vavasseur"
    },
    {
      "affiliations": [
        "Digestive Physiology, Hospices Civils de Lyon, Hopital E Herriot, F-69437, Lyon, France",
        "Digestive Physiology, Lyon I University, F-69008, Lyon, France",
        "LabTAU, INSERM, Université Lyon 1, Univ Lyon, F-69003, Lyon, France"
      ],
      "name": "Sabine Roman"
    },
    {
      "affiliations": [
        "Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China",
        "Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China"
      ],
      "name": "Pinghong Zhou"
    },
    {
      "affiliations": [
        "Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China",
        "Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China"
      ],
      "name": "Quanlin Li"
    },
    {
      "affiliations": [
        "Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China",
        "Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China"
      ],
      "name": "Zuqiang Liu"
    },
    {
      "affiliations": [
        "Department of Surgery, Paracelsus Medical University, Salzburg, Austria"
      ],
      "name": "Burkhard H A von Rahden"
    },
    {
      "affiliations": [
        "Foregut Surgery Department, Hippokration General Hospital of Athens, Athens, Greece"
      ],
      "name": "Dimitris Theodorou"
    },
    {
      "affiliations": [
        "Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland"
      ],
      "name": "Ewa Malecka-Wojciesko"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University of Marburg, Marburg, Germany"
      ],
      "name": "Carlo Maj"
    },
    {
      "affiliations": [
        "Lab-Genetics and molecular basis of complex diseases, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain"
      ],
      "name": "Ana G Vigo"
    },
    {
      "affiliations": [
        "Institute of Physiology, Charles University in Prague, Prague, Czech Republic",
        "Department of Gastroenterology and Hepatology, St. Anne University Hospital, Brno, Czech Republic",
        "Faculty of Medicine, Ostrava University, Ostrava, Czech Republic"
      ],
      "name": "Jan Martinek"
    },
    {
      "affiliations": [
        "Laboratory for Intestinal Neuroimmune Interactions, Translational Research Center for Gastrointestinal Disorders, KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium"
      ],
      "name": "Guy Boeckxstaens"
    },
    {
      "affiliations": [
        "Institute of Human Genetics, University of Marburg, Marburg, Germany"
      ],
      "name": "Johannes Schumacher"
    }
  ],
  "title": "First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia",
  "uid": "e3cc70d4-5246-5235-8885-6ca55a5c7fb3"
}