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

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 (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).

This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology.