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. 2025 Nov 12:gutjnl-2024-334498.
doi: 10.1136/gutjnl-2024-334498. Online ahead of print.

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

Sandeep Grover #  1 , Ines Gockel #  2 , Anna Latiano #  3 , Anna Mokrowiecka #  4 , Pouria Dasmeh  1 , Mira M Wouters  5 , Zuzana Vackova  6 , Stephan L Haas  7 , Tania Triantafyllou  8 , Nicole Kreuser  2 , Jessica Trautmann  9 , Stefan Niebisch  2 , Timo Hess  1 , Rene Thieme  2 , Jessica Bigge  1 , Hubert Louis  10 , Eric Quertinmont  11 , Aline Meirhaeghe  12 , Manon Muntaner  12 , Philippe Amouyel  12 , Guillaume Gourcerol  13 , Stanislas Bruley des Varannes  14 , Francois Mion  15   16   17 , Michael Vieth  18 , Nikolaos Scarmeas  19   20 , Orazio Palmieri  3 , Francesca Tavano  3 , Roberto De Giorgio  21 , Daniela Galimberti  22   23 , Andrea Arighi  23 , Beatrice Arosio  23   24 , Marco Bruno  25 , Justyna Wasielica-Berger  26 , Magdalena Gawron-Kiszka  27 , Maria Janiak  28 , Magdalena Siepsiak  28 , Krystian Adrych  28 , Tomasz Marek  27 , Andrzej Dabrowski  26 , Marek Majewski  29 , Piotr Gietka  30 , Maciej Gonciarz  30 , Julio Pérez de la Serna  31 , Laisy Zacarías Martínez  32 , Vilmantas Giedraitis  33 , Lena Kilander  33 , Laura Fratiglioni  34 , Luis Miguel Real  35   36   37 , Julius Spicak  6 , Jan Tack  38   39 , Stefanie Heilmann-Heimbach  9   40 , Markus Nöthen  9 , Martin Ingelsson  41   42   43 , Caroline Graff  44   45 , Agustín Ruiz  46   47   48 , Jean-Charles Lambert  12 , Alfredo Ramirez  49   50   51   52   53 , Alexander J Eckardt  54 , Michaela Müller  55 , Michael Knapp  56 , Thaddäus T Wissinowski  57 , Jutta Keller  58 , Christiane Josephine Bruns  59 , Christian Gerges  60 , Horst Neuhaus  61 , Thomas Rösch  62 , Britta Siegmund  63 , Brigitte Schumacher  64 , Marino Venerito  65 , Antonio Ruiz de León  31 , Riccardo Rosati  66 , Vito Annese  67 , Uberto Fumagalli  68 , Luigi Laghi  69 , Elena Urcelay  70 , Fabienne Vavasseur  14 , Sabine Roman  15   16   17 , Pinghong Zhou  71   72 , Quanlin Li  71   72 , Zuqiang Liu  71   72 , Burkhard H A von Rahden  73 , Dimitris Theodorou  8 , Ewa Malecka-Wojciesko  4 , Carlo Maj  1 , Ana G Vigo #  70 , Jan Martinek #  74   75   76 , Guy Boeckxstaens #  5 , Johannes Schumacher #  77
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Free article

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

Sandeep Grover et al. Gut. .
Free article

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.

Keywords: ACHALASIA; GENETIC POLYMORPHISMS; GENETICS; HLA CLASS II ALLELES; RNA EXPRESSION.

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Conflict of interest statement

Competing interests: MBr has declared the following conflicts of interest: he has received consultancy fees and support for both industry and investigator-initiated studies from Boston Scientific and Cook Medical. He has also served as a consultant and received support for investigator-initiated studies from Pentax Medical and AMBU. Additionally, he has received support for investigator-initiated studies from Mylan and ChiRoStim. BSi consulted for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Landos, Lilly, Materia Prima, PredictImmune, Pfizer and Takeda. BSi also received speaker fees from AbbVie, AlfaSigma, BMS, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Janssen, Pfizer and Takeda. Additionally, BSi was supported in the past by grants from Pfizer. GBo and TRö hold positions as Editor or an Editorial Board Member of the journal GUT. The remaining authors declare no competing interests.