Identification of risk-genes for achalasia

• Applicants: Professorin Dr. Ines Gockel; Privatdozent Dr. Michael Knapp; Professor Dr. Johannes Schumacher
• Subject Area: Human Genetics
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 230840675

Achalasia represents a severe disorder that affects the lower esophageal sphincter (LES). Physiologically, the LES is contracted and prevents reflux of gastric acid into the esophagus. The LES relaxes and opens only on swallowing, allowing the ingested food entering the stomach. In achalasia, this relaxation is increasingly restricted, so the food cannot be transported into the stomach. The result is the development of a megaesophagus with irreversible functional loss of the LES and the esophageal peristalsis. In addition, the retention of food can lead to aspiration pneumonia and esophagitis, which represents a precancerous condition for the development of an esophageal carcinoma.The persistent contraction of the LES is caused by the degeneration of neurons in the myenteric plexus, which controls the motility of the intestinal tract. This affects mainly neurons that have an inhibitory effect on the LES. Although this provides the first insight into the disease pathophysiology, the underlying causes of the selective neurodegeneration in the myenteric plexus are poorly understood. It is thought that genetic susceptibility factors in many genes are significant in the disease process.The applicant Prof. Ines Gockel leads the achalasia risk consortium arc (www.achalasie-konsortium.de), which is an initiative of scientists and aims to elucidate the genetic and cell biological causes of achalasia. Through arc the applicants have collected the world-wide largest cohort of achalasia patients (N=1,000). A part of this collective (N=638) has been already applied to a genome-wide association study (GWAS) using the so called ImmunoChips as SNP array. Through GWAS up to 1 M genetic variants can be systematically analyzed. By comparing the genotype distribution between patients and controls this allows the identification of risk genes in a hypothesis-free manner. Accordingly, the applicants have identified the first genetic risk factors for achalasia using a part of their achalasia collective for a GWAS. Based on these results, further GWAS on all achalasia patients are planned which will lead most comprehensively to the identification of further achalasia risk genes. This case-control cohort (N=1,000 patients, N =2,336 controls) will be analyzed using three different SNP arrays. This should allow the identification of different risk variants (frequent and rare SNPs and CNVs), which are involved in the disease etiology.Upon approval of this application arc could be placed in an international leading position in the field of molecular genetic research on achalasia. In addition, the consortium provides an excellent basis for the elucidation of the pathophysiology of achalasia after the first risk gens have been identified.

• DFG Programme: Research Grants