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@ARTICLE{Grover:285361,
      author       = {Grover, Sandeep and Gockel, Ines and Latiano, Anna and
                      Mokrowiecka, Anna and Dasmeh, Pouria and Wouters, Mira M and
                      Vackova, Zuzana and Haas, Stephan L and Triantafyllou, Tania
                      and Kreuser, Nicole and Trautmann, Jessica and Niebisch,
                      Stefan and Hess, Timo and Thieme, Rene and Bigge, Jessica
                      and Louis, Hubert and Quertinmont, Eric and Meirhaeghe,
                      Aline and Muntaner, Manon and Amouyel, Philippe and
                      Gourcerol, Guillaume and Bruley des Varannes, Stanislas and
                      Mion, Francois and Vieth, Michael and Scarmeas, Nikolaos and
                      Palmieri, Orazio and Tavano, Francesca and De Giorgio,
                      Roberto and Galimberti, Daniela and Arighi, Andrea and
                      Arosio, Beatrice and Bruno, Marco and Wasielica-Berger,
                      Justyna and Gawron-Kiszka, Magdalena and Janiak, Maria and
                      Siepsiak, Magdalena and Adrych, Krystian and Marek, Tomasz
                      and Dabrowski, Andrzej and Majewski, Marek and Gietka, Piotr
                      and Gonciarz, Maciej and Pérez de la Serna, Julio and
                      Martínez, Laisy Zacarías and Giedraitis, Vilmantas and
                      Kilander, Lena and Fratiglioni, Laura and Real, Luis Miguel
                      and Spicak, Julius and Tack, Jan and Heilmann-Heimbach,
                      Stefanie and Nöthen, Markus and Ingelsson, Martin and
                      Graff, Caroline and Ruiz, Agustín and Lambert, Jean-Charles
                      and Ramirez, Alfredo and Eckardt, Alexander J and Müller,
                      Michaela and Knapp, Michael and Wissinowski, Thaddäus T and
                      Keller, Jutta and Bruns, Christiane Josephine and Gerges,
                      Christian and Neuhaus, Horst and Rösch, Thomas and
                      Siegmund, Britta and Schumacher, Brigitte and Venerito,
                      Marino and Ruiz de León, Antonio and Rosati, Riccardo and
                      Annese, Vito and Fumagalli, Uberto and Laghi, Luigi and
                      Urcelay, Elena and Vavasseur, Fabienne and Roman, Sabine and
                      Zhou, Pinghong and Li, Quanlin and Liu, Zuqiang and Rahden,
                      Burkhard H A von and Theodorou, Dimitris and
                      Malecka-Wojciesko, Ewa and Maj, Carlo and Vigo, Ana G and
                      Martinek, Jan and Boeckxstaens, Guy and Schumacher,
                      Johannes},
      title        = {{F}irst genome-wide association study reveals
                      immune-mediated aetiopathology in idiopathic achalasia.},
      journal      = {Gut},
      volume       = {75},
      number       = {3},
      issn         = {0017-5749},
      address      = {London},
      publisher    = {BMJ Publishing Group},
      reportid     = {DZNE-2026-00226},
      pages        = {476 - 485},
      year         = {2025},
      abstract     = {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.},
      keywords     = {ACHALASIA (Other) / GENETIC POLYMORPHISMS (Other) /
                      GENETICS (Other) / HLA CLASS II ALLELES (Other) / RNA
                      EXPRESSION (Other)},
      cin          = {Patient Studies (Bonn)},
      ddc          = {610},
      cid          = {I:(DE-2719)1011101},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41136183},
      doi          = {10.1136/gutjnl-2024-334498},
      url          = {https://pub.dzne.de/record/285361},
}