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

Sandeep Grover; Ines Gockel; Anna Latiano; Anna Mokrowiecka; Pouria Dasmeh; Mira M. Wouters; Zuzana Vackova; Stephan L. Haas; Tania Triantafyllou; Nicole Kreuser; Jessica Trautmann; Stefan Niebisch; Timo Hess; Rene Thieme; Jessica Bigge; Hubert Louis; Eric Quertinmont; Aline Meirhaeghe; Manon Muntaner; Philippe Amouyel; Guillaume Gourcerol; Stanislas Bruley Des Varannes; Francois Mion; Michael Vieth; Nikolaos Scarmeas; Orazio Palmieri; Francesca Tavano; Roberto De Giorgio; Daniela Galimberti; Andrea Arighi; Beatrice Arosio; Marco Bruno; Justyna Wasielica-Berger; Magdalena Gawron-Kiszka; Maria Janiak; Magdalena Siepsiak; Krystian Adrych; Tomasz Marek; Andrzej Dabrowski; Marek Majewski; Piotr Gietka; Maciej Gonciarz; Julio Pérez De La Serna; Laisy Zacarías Martínez; Vilmantas Giedraitis; Lena Kilander; Laura Fratiglioni; Luis Miguel Real; Julius Spicak; Jan Tack; Stefanie Heilmann-Heimbach; Markus Nöthen; Martin Ingelsson; Caroline Graff; Agustín Ruiz; Jean Charles Lambert; Alfredo Ramirez; Alexander J. Eckardt; Michaela Müller; Michael Knapp; Thaddäus T. Wissinowski; Jutta Keller; Christiane Josephine Bruns; Christian Gerges; Horst Neuhaus; Thomas Rösch; Britta Siegmund; Brigitte Schumacher; Marino Venerito; Antonio Ruiz De León; Riccardo Rosati; Vito Annese; Uberto Fumagalli; Luigi Laghi; Elena Urcelay; Fabienne Vavasseur; Sabine Roman; Pinghong Zhou; Quanlin Li; Zuqiang Liu; Burkhard H.A.von Rahden; Dimitris Theodorou; Ewa Malecka-Wojciesko; Carlo Maj; Ana G. Vigo; Jan Martinek; Guy Boeckxstaens; Johannes Schumacher

doi:10.1136/gutjnl-2024-334498

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

Sandeep Grover
, Ines Gockel
, Anna Latiano
, Anna Mokrowiecka
, Pouria Dasmeh
, Mira M. Wouters
, Zuzana Vackova
, Stephan L. Haas
, Tania Triantafyllou
, Nicole Kreuser
, Jessica Trautmann
, Stefan Niebisch
, Timo Hess
, Rene Thieme
, Jessica Bigge
, Hubert Louis
, Eric Quertinmont
, Aline Meirhaeghe
, Manon Muntaner
, Philippe Amouyel

Guillaume Gourcerol, Stanislas Bruley Des Varannes, Francois Mion, Michael Vieth, Nikolaos Scarmeas, Orazio Palmieri, Francesca Tavano, Roberto De Giorgio, Daniela Galimberti, Andrea Arighi, Beatrice Arosio, Marco Bruno, Justyna Wasielica-Berger, Magdalena Gawron-Kiszka, Maria Janiak, Magdalena Siepsiak, Krystian Adrych, Tomasz Marek, Andrzej Dabrowski, Marek Majewski, Piotr Gietka, Maciej Gonciarz, Julio Pérez De La Serna, Laisy Zacarías Martínez, Vilmantas Giedraitis, Lena Kilander, Laura Fratiglioni, Luis Miguel Real, Julius Spicak, Jan Tack, Stefanie Heilmann-Heimbach, Markus Nöthen, Martin Ingelsson, Caroline Graff, Agustín Ruiz, Jean Charles Lambert, Alfredo Ramirez, Alexander J. Eckardt, Michaela Müller, Michael Knapp, Thaddäus T. Wissinowski, Jutta Keller, Christiane Josephine Bruns, Christian Gerges, Horst Neuhaus, Thomas Rösch, Britta Siegmund, Brigitte Schumacher, Marino Venerito, Antonio Ruiz De León, Riccardo Rosati, Vito Annese, Uberto Fumagalli, Luigi Laghi, Elena Urcelay, Fabienne Vavasseur, Sabine Roman, Pinghong Zhou, Quanlin Li, Zuqiang Liu, Burkhard H.A.von Rahden, Dimitris Theodorou, Ewa Malecka-Wojciesko, Carlo Maj, Ana G. Vigo, Jan Martinek, Guy Boeckxstaens, Johannes Schumacher^*

^*Corresponding author for this work

Gastroenterology & Hepatology

Universität Marburg
University Hospital Leipzig
IRCCS Ospedale Casa Sollievo della Sofferenza - San Giovanni Rotondo (FG)
Medical University of Łódź
KU Leuven
Institute for Clinical and Experimental Medicine
Karolinska Institutet
Hippokration General Hospital
University Hospital Bonn
Université libre de Bruxelles
Université de Lille
Digestive Physiology Department
CHU de Nantes
Hôpital Édouard Herriot
Universite Claude Bernard Lyon 1
Université Lyon 1
Friedrich-Alexander University Erlangen-Nürnberg
National and Kapodistrian University of Athens
Columbia University
University of Ferrara
University of Milan
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
Medical University of Białystok
Medical University of Silesia in Katowice
Medical University of Gdańsk
Medical University of Lublin
Wojskowy Instytut Medyczny
Hospital Clínico San Carlos de Madrid
Generalitat de Catalunya
Uppsala University
Hospital Universitario de Valme
University of Seville
Centro de Investigación Biomédica en Red (CIBER)
University Hospitals Leuven
University of Bonn
University Health Network
University of Toronto
Karolinska University Hospital
University of Texas Health Science Center at San Antonio
Ace Alzheimer Center Barcelona
Instituto de Salud Carlos III
University Hospital Cologne
German Center for Neurodegenerative Diseases
University of Cologne
Gastro-Praxis Wiesbaden
Klinikum Chemnitz gGmbH
Israelitisches Krankenhaus Hamburg
University Hospital Essen
Evangelisches Krankenhaus Düsseldorf
University Medical Center Hamburg-Eppendorf
Charité – Universitätsmedizin Berlin
Elisabeth-Krankenhaus Essen
Otto von Guericke University Magdeburg
Vita-Salute San Raffaele University
University of Florence
IRCCS Istituto Clinico Humanitas - Rozzano (Milano)
Fudan University
Shanghai Collaborative Innovation Center of Endoscopy
Paracelsus Private Medical University
Charles University
Masaryk University
University of Ostrava

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

8 Citations (Scopus)

11 Downloads (Pure)

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.

Original language	English
Pages (from-to)	476-485
Number of pages	10
Journal	Gut
Volume	75
Issue number	3
DOIs	https://doi.org/10.1136/gutjnl-2024-334498
Publication status	Published - 1 Mar 2026

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2026.

Access to Document

10.1136/gutjnl-2024-334498Licence: CC BY-NC

476.fullFinal published version, 935 KBLicence: CC BY-NC

Cite this

Grover, S., Gockel, I., Latiano, A., Mokrowiecka, A., Dasmeh, P., Wouters, M. M., Vackova, Z., Haas, S. L., Triantafyllou, T., Kreuser, N., Trautmann, J., Niebisch, S., Hess, T., Thieme, R., Bigge, J., Louis, H., Quertinmont, E., Meirhaeghe, A., Muntaner, 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

@article{f8e8c60bf91e4a288fe9dfffe34d578e,

title = "First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia",

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{\texttimes}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{\texttimes}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{\texttimes}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{\texttimes}10 -19). Conclusion This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology.",

author = "Sandeep Grover and Ines Gockel and Anna Latiano and Anna Mokrowiecka and Pouria Dasmeh and Wouters, \{Mira M.\} and Zuzana Vackova and Haas, \{Stephan L.\} and Tania Triantafyllou and Nicole Kreuser and Jessica Trautmann and Stefan Niebisch and Timo Hess and Rene Thieme and Jessica Bigge and Hubert Louis and Eric Quertinmont and Aline Meirhaeghe and Manon Muntaner and Philippe Amouyel and Guillaume Gourcerol and \{Bruley Des Varannes\}, Stanislas and Francois Mion and Michael Vieth and Nikolaos Scarmeas and Orazio Palmieri and Francesca Tavano and \{De Giorgio\}, Roberto and Daniela Galimberti and Andrea Arighi and Beatrice Arosio and Marco Bruno and Justyna Wasielica-Berger and Magdalena Gawron-Kiszka and Maria Janiak and Magdalena Siepsiak and Krystian Adrych and Tomasz Marek and Andrzej Dabrowski and Marek Majewski and Piotr Gietka and Maciej Gonciarz and \{P{\'e}rez De La Serna\}, Julio and Mart{\'i}nez, \{Laisy Zacar{\'i}as\} and Vilmantas Giedraitis and Lena Kilander and Laura Fratiglioni and Real, \{Luis Miguel\} and Julius Spicak and Jan Tack and Stefanie Heilmann-Heimbach and Markus N{\"o}then and Martin Ingelsson and Caroline Graff and Agust{\'i}n Ruiz and Lambert, \{Jean Charles\} and Alfredo Ramirez and Eckardt, \{Alexander J.\} and Michaela M{\"u}ller and Michael Knapp and Wissinowski, \{Thadd{\"a}us T.\} and Jutta Keller and Bruns, \{Christiane Josephine\} and Christian Gerges and Horst Neuhaus and Thomas R{\"o}sch and Britta Siegmund and Brigitte Schumacher and Marino Venerito and \{Ruiz De Le{\'o}n\}, Antonio and Riccardo Rosati and Vito Annese and Uberto Fumagalli and Luigi Laghi and Elena Urcelay and Fabienne Vavasseur and Sabine Roman and Pinghong Zhou and Quanlin Li and Zuqiang Liu and Rahden, \{Burkhard H.A.von\} and Dimitris Theodorou and Ewa Malecka-Wojciesko and Carlo Maj and Vigo, \{Ana G.\} and Jan Martinek and Guy Boeckxstaens and Johannes Schumacher",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2026.",

year = "2026",

month = mar,

day = "1",

doi = "10.1136/gutjnl-2024-334498",

language = "English",

volume = "75",

pages = "476--485",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "3",

}

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, BHAV, Theodorou, D, Malecka-Wojciesko, E, Maj, C, Vigo, AG, Martinek, J, Boeckxstaens, G & Schumacher, J 2026, 'First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia', Gut, vol. 75, no. 3, pp. 476-485. https://doi.org/10.1136/gutjnl-2024-334498

TY - JOUR

T1 - First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia

AU - Grover, Sandeep

AU - Gockel, Ines

AU - Latiano, Anna

AU - Mokrowiecka, Anna

AU - Dasmeh, Pouria

AU - Wouters, Mira M.

AU - Vackova, Zuzana

AU - Haas, Stephan L.

AU - Triantafyllou, Tania

AU - Kreuser, Nicole

AU - Trautmann, Jessica

AU - Niebisch, Stefan

AU - Hess, Timo

AU - Thieme, Rene

AU - Bigge, Jessica

AU - Louis, Hubert

AU - Quertinmont, Eric

AU - Meirhaeghe, Aline

AU - Muntaner, Manon

AU - Amouyel, Philippe

AU - Gourcerol, Guillaume

AU - Bruley Des Varannes, Stanislas

AU - Mion, Francois

AU - Vieth, Michael

AU - Scarmeas, Nikolaos

AU - Palmieri, Orazio

AU - Tavano, Francesca

AU - De Giorgio, Roberto

AU - Galimberti, Daniela

AU - Arighi, Andrea

AU - Arosio, Beatrice

AU - Bruno, Marco

AU - Wasielica-Berger, Justyna

AU - Gawron-Kiszka, Magdalena

AU - Janiak, Maria

AU - Siepsiak, Magdalena

AU - Adrych, Krystian

AU - Marek, Tomasz

AU - Dabrowski, Andrzej

AU - Majewski, Marek

AU - Gietka, Piotr

AU - Gonciarz, Maciej

AU - Pérez De La Serna, Julio

AU - Martínez, Laisy Zacarías

AU - Giedraitis, Vilmantas

AU - Kilander, Lena

AU - Fratiglioni, Laura

AU - Real, Luis Miguel

AU - Spicak, Julius

AU - Tack, Jan

AU - Heilmann-Heimbach, Stefanie

AU - Nöthen, Markus

AU - Ingelsson, Martin

AU - Graff, Caroline

AU - Ruiz, Agustín

AU - Lambert, Jean Charles

AU - Ramirez, Alfredo

AU - Eckardt, Alexander J.

AU - Müller, Michaela

AU - Knapp, Michael

AU - Wissinowski, Thaddäus T.

AU - Keller, Jutta

AU - Bruns, Christiane Josephine

AU - Gerges, Christian

AU - Neuhaus, Horst

AU - Rösch, Thomas

AU - Siegmund, Britta

AU - Schumacher, Brigitte

AU - Venerito, Marino

AU - Ruiz De León, Antonio

AU - Rosati, Riccardo

AU - Annese, Vito

AU - Fumagalli, Uberto

AU - Laghi, Luigi

AU - Urcelay, Elena

AU - Vavasseur, Fabienne

AU - Roman, Sabine

AU - Zhou, Pinghong

AU - Li, Quanlin

AU - Liu, Zuqiang

AU - Rahden, Burkhard H.A.von

AU - Theodorou, Dimitris

AU - Malecka-Wojciesko, Ewa

AU - Maj, Carlo

AU - Vigo, Ana G.

AU - Martinek, Jan

AU - Boeckxstaens, Guy

AU - Schumacher, Johannes

PY - 2026/3/1

Y1 - 2026/3/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105030188417

U2 - 10.1136/gutjnl-2024-334498

DO - 10.1136/gutjnl-2024-334498

M3 - Article

C2 - 41136183

AN - SCOPUS:105030188417

SN - 0017-5749

VL - 75

SP - 476

EP - 485

JO - Gut

JF - Gut

IS - 3

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this