Identification of causal genes and cellular pathways for idiopathic achalasia on the basis of genome-wide association studies (GWAS)

• Applicants: Privatdozent Dr. Michael Knapp; Professor Dr. Markus M. Nöthen, since 7/2018
• Subject Area: Human Genetics
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386793983

Idiopathic achalasia represents a primary motility disorder of the esophagus. It is characterized by esophageal aperistalsis and a failure of the lower esophageal sphincter (LES) to relax due to a loss of inhibitory neurons in the myenteric plexus. Although the pathophysiology of this neuronal degeneration is mainly unknown, autoimmune processes seem to be involved in individuals with a genetic susceptibility. On the etiology level, achalasia is multifactorial and involves a combination of the cumulative effect of variants in various risk genes and environmental factors. Recently, we have conducted the first systematic association studies in case control samples with achalasia using the Illumina ImmunoChip that contains > 190 K single nucleotide polymorphisms (SNPs) in genomic regions that previously showed association to various autoimmune diseases. This revealed that an 8-amino-acid insertion in the cytoplasmic tail of the HLA-DQ receptor confers the strongest risk for achalasia (Gockel et al. (2014) Nat Genet 46: 901-904). Furthermore, two amino acid substitutions in the extracellular domain of the HLA-DQ receptor independently confer achalasia risk. In addition, we have shown that the 8-amino-acid insertion in the HLA-DQ receptor is less common in Northern compared to Southern Europeans (Becker et al. (2016) Eur J Hum Genet 24: 1228-1231). This geospatial north-south gradient implies that the prevalence of idiopathic achalasia may differ among populations. The aim of this project is the comprehensive identification of further genetic risk variants for idiopathic achalasia. For this purpose, a genome-wide association study (GWAS) will be carried out using 5,000 European patients as well as 6,346 ethnically matched controls. Identified risk variants will be followed up by in silico functional studies in order to determine their cellular function and to identify disease relevant biological pathways. The identified risk variants and pathways represent important prerequisites for future functional studies in order to elucidate the biological basis of achalasia. In addition, the achalasia GWAS data will be analyzed jointly using GWAS data for other autoimmune diseases. Furthermore, genotype-phenotype (GxP) studies will be carried out using the achalasia GWAS data and detailed collected phenotypic data from patients. These data will allow to estimate the genetic correlation between achalasia and other autoimmune disorders as well as the identification of biologically based subtypes of achalasia. The applied project does not end with the GWAS. By our own work and in cooperation with other scientist, the identified risk variants will be functionally analyzed, which will help to elucidate the pathophysiology of achalasia.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Johannes Schumacher, until 6/2018