TY  - JOUR
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
TI  - First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia.
JO  - Gut
VL  - 75
IS  - 3
SN  - 0017-5749
CY  - London
PB  - BMJ Publishing Group
M1  - DZNE-2026-00226
SP  - 476 - 485
PY  - 2025
AB  - 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.This study aimed to uncover the genetic risk architecture of IA.We carried out the first genome-wide association study (GWAS) on 4602 European patients with IA and 10 766 ethnically-matched controls.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).This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology.
KW  - ACHALASIA (Other)
KW  - GENETIC POLYMORPHISMS (Other)
KW  - GENETICS (Other)
KW  - HLA CLASS II ALLELES (Other)
KW  - RNA EXPRESSION (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41136183
DO  - DOI:10.1136/gutjnl-2024-334498
UR  - https://pub.dzne.de/record/285361
ER  -