First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia

Grover S, Gockel I, Latiano A, Mokrowiecka A, Dasmeh P, Wouters MM, Vackova Z, Haas SL, Triantafyllou T, Kreuser N, Trautmann J, Niebisch S, Hess T, Thieme R, Bigge J, Louis H, Quertinmont E, Meirhaeghe A, Muntaner M, Amouyel P, Gourcerol G, Bruley Des Varannes S, Mion F, Vieth M, Scarmeas N, Palmieri O, Tavano F, De Giorgio R, Galimberti D, Arighi A, Arosio B, Bruno M, Wasielica-Berger J, Gawron-Kiszka M, Janiak M, Siepsiak M, Adrych K, Marek T, Dabrowski A, Majewski M, Gietka P, Gonciarz M, Pérez De La Serna J, Martínez LZ, Giedraitis V, Kilander L, Fratiglioni L, Real LM, Spicak J, Tack J, Heilmann-Heimbach S, Nöthen M, Ingelsson M, Graff C, Ruiz A, Lambert JC, Ramirez A, Eckardt AJ, Müller M, Knapp M, Wissinowski TT, Keller J, Bruns CJ, Gerges C, Neuhaus H, Rösch T, Siegmund B, Schumacher B, Venerito M, Ruiz De León A, Rosati R, Annese V, Fumagalli U, Laghi L, Urcelay E, Vavasseur F, Roman S, Zhou P, Li Q, Liu Z, Rahden BH, Theodorou D, Malecka-Wojciesko E, Maj C, Vigo AG, Martinek J, Boeckxstaens G, Schumacher J (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 75

Pages Range: 476-485

Journal Issue: 3

DOI: 10.1136/gutjnl-2024-334498

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 (r g =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 with CRIS profile

Involved external institutions

Medical University of Bialystok Poland (PL) Charité - Universitätsmedizin Berlin Germany (DE) Elisabeth-Krankenhaus Essen Germany (DE) University of Rouen / Université de Rouen France (FR) Università degli studi di Milano Italy (IT) Hôpital Edouard Herriot France (FR) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Casa Sollievo della Sofferenza Italy (IT) Otto-von-Guericke-Universität Magdeburg Germany (DE) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Humanitas Research Hospital / IRCCS Istituto Clinico Humanitas Italy (IT) Università degli Studi di Ferrara Italy (IT) Hospital Clínico San Carlos Spain (ES) Philipps-Universität Marburg Germany (DE) Universitätsklinikum Leipzig Germany (DE) Medical University of Łódź / Uniwersytet Medyczny w Łodzi Poland (PL) Evangelisches Krankenhaus Düsseldorf Germany (DE) Institute for Clinical and Experimental Medicine (IKEM) Czech Republic (CZ) Karolinska Institute Sweden (SE) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Köln Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Klinikum Chemnitz Germany (DE) Israelitisches Krankenhaus Hamburg Germany (DE) Universitätsklinikum Essen Germany (DE) Erasmus University Medical Center (MC) Netherlands (NL) Università Vita-Salute San Raffaele (UniSR) Italy (IT) Università degli Studi di Firenze / University of Florence Italy (IT) Fudan University / 复旦大学 China (CN) Paracelsus Medizinische Privatuniversität Austria (AT) "Hippokration" General Hospital of Athens, Medical School Greece (GR) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) Medical University of Silesia in Katowice / Śląski Uniwersytet Medyczny w Katowicach (SUM) Poland (PL) Medical University Gdansk / Gdański Uniwersytet Medyczny Poland (PL) Hôpital Erasme Belgium (BE) Université libre de Bruxelles (ULB) / Free University of Brussels Belgium (BE) Université de Lille (ULille, UDL) France (FR) Medical University of Lublin / Uniwersytet Medyczny w Lublinie Poland (PL) Wojskowy Instytut Medyczny Poland (PL) Health Sciences Research Institute of the “Germans Trias i Pujol” Foundation (IGTP) Spain (ES) Hospital Universitario Virgen de Valme Spain (ES) University of Texas Health Science Center at San Antonio (UTHSCSA) United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE)

How to cite

APA:

Grover, S., Gockel, I., Latiano, A., Mokrowiecka, A., Dasmeh, P., Wouters, M.M.,... Schumacher, J. (2026). First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia. Gut, 75(3), 476-485. https://doi.org/10.1136/gutjnl-2024-334498

MLA:

Grover, Sandeep, et al. "First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia." Gut 75.3 (2026): 476-485.

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