SP 1

Monogenic and oligogenic traits as an entry port to systems medicine

This project is based on the observation that complex traits as defined by traditional criteria include cases with a Mendelian component and monogenic cases. Mendelian components can serve as models to study fundamental molecular disease processes. Further, there are genes that exhibit only rare variants which are missed by classical complex genetics approaches.

Molecular genetics of complex traits: rare mono- and oligogenic forms can be used to map and charactize genetic defects that lead to specific phenotypic features

Via large and cumulative effects uch rare variants can have a major impact on disease development. The systematic investigation of mono- and oligigenic disturbances can thus provide deeper insights into the aetiopathogenesis of complex traits than genome-wide association studies and contribute to the development of more rational disease classifications and preventive and therapeutic approaches. Within the scope of this project the heterogeneity of chronic inflammatory barrier diseases shall be reduced by stratification of existing disease collections using clinical and molecular profiles.

Chronic-inflammtory barrier diseases: certain genetically influenced molecular mechanisms such as epithelial deficiencies and inflammatory reactions drive barrier diseases.

Biomarkers for re-classification of disease groups shall be developed. To this end, homogenous subgroups of patients and families with suggestive evidence for the presence of mono and ologogenic defects will undergo deep characterization to identify causal gene variants. Patients with known monogenic immune deficiencies and accompanying chronic inflammatory
barrier diseases will be examined in depth, and the molecular mechanisms of selected gene defects will be investigated in vitro and using animal models.

Co-Operation partners:
Prof. Dr. med. Michael Kabesch (Regensburg, www.mh-hannover.de/16105.html)
Prof. Bodo Grimbacher (Freiburg, www.zse-freiburg.de/de/CC)

Strategies used in this project: Key mechansims of chronic inflammatory barrier diseases shall be elucidated by re-analysing existing clinical and molecular data disease collections and in-depth examination of patients with known monogenic immune deficiencies and accompanying chronic inflammatory barrier diseases.

Keywords: Monogenic, oligogenic, complex traits