Identification of genetic risk variants for inflammatory bowel disease (IBD)

• Applicant: Dr. Anna B. Stittrich
• Subject Area: Human Genetics
• Term: from 2014 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261754005

Most complex diseases are partly rooted in the genome. Inflammatory bowel disease (IBD) is a complex disorder encompassing chronic inflammatory conditions of the colon and the small intestine. The two major types of IBD are Crohn's disease and ulcerative colitis. The cause of IBD remains unknown but genetic predisposition accounts for up to 50% of disease cases. Linkage and genome-wide association studies (GWAS) have associated many genetic regions with IBD. However, these associations are weak and fall short in explaining the observed heritability. Furthermore, it remains mostly elusive which variants are mechanistically responsible for the associations because of the low resolution of these studies. As a result the known IBD risk loci are insufficient to predict disease or explain disease etiology. I propose to apply whole-genome sequencing to identify new IBD risk variants. I will analyze families with a high incidence of IBD, which is why this study has the power to identify causative genetic variants that have strong effects and moderate to high penetrance. I will validate the candidate risk variants epidemiologically and experimentally. For epidemiologic validation I will identify the candidate harboring haplotypes and determine the haplotype-specific patterns of single nucleotide polymorphisms (SNPs). Using these SNP patterns I will infer the candidate variants in existing GWAS data sets and test for segregation with IBD. For functional validation I will use blood samples from the sequenced families and analyze transcript levels of the genes affected by my candidate variants. Moreover, I will experimentally assess the function of the candidates and I will test if they affect immune regulation or barrier function. My preliminary results indicate that this study can reveal new IBD risk variants, which will help to explain heritability and understand IBD etiology.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Leroy Hood, Ph.D.