Whole Exome Sequencing of Crohn's Disease Pedigrees

• Applicant: Professor Dr. Andre Franke
• Subject Area: Gastroenterology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249995099

Crohn's disease (CD) is a complex, chronic inflammatory bowel disease (IBD). A variety of genetic and environmental factors likely play a role in causing CD. Genome-wide association studies (GWAS) and meta-analyses have so far identified 71 susceptibility loci for CD. These, however, explain only 23% of the heritability so far. Therefore, to identify further sources of heritability, other approaches apart from case-control SNP-based association studies are needed. While GWAS successfully identified common variants with small effect sizes, the detection of rare susceptibility variants with high penetrance needs to be performed by systematic resequencing studies. The applicant's institute has immediate access to a large number of samples from families with CD. By using the locally established NGS-based whole exome sequencing approach, it is planned to identify further susceptibility variants. 50 samples will be sequenced: 40 affected and 10 healthy individuals of ~10 pedigrees with at least two affected individuals within the same pedigree, which allows identifying overlaps between the affected and hence inherited mutations. Large case-control collections (>15,000 patients and >27,000 healthy control samples) are in place to validate and replicate the identified mutations and to screen the identified susceptibility genes for further variants of interest. Validated variants will then be studied further by basic functional follow-up studies for identifying the disease-causing molecular mechanisms.

• DFG Programme: Research Grants