"ChIP Seq RA CD"""" · Identification of regulator variants in Rheumatoid Arthritis and Crohn’s Disease

Identification of regulator variants in Rheumatoid Arthritis and Crohn’s Disease

Genome-wide association studies (GWAS) which were extensively used to identify genetic risk variants in human complex disease such as Crohn’s disease (CD) and Rheumatoid Arthritis (RA), have uncovered dozens of risk alleles in aggregate explaining ~10-15% of heritability. However, the molecular mechanisms underlying these associations remain elusive. The major reason is that only a small fraction of trait-associated variants can be linked to coding sequences. It was speculated that many of the underlying causal alleles impact regulatory elements (such as promoters or enhancers) which control the expression of proximal or distal genes. The identification of regulatory elements influenced by risk variants involves assaying epigenetic chromatin marks, which correspond to chemical modifications of histone that alter the chromatin structure to allow access to the transcriptional machinery. A practical challenge is that there are hundreds of chromatin marks which might be potentially assayed, and that it is prohibitive to conduct studies on all of them in large numbers of different tissues or in samples collected from many individuals. However, because chromatin marks provide redundant information, the status of a small subset of the most informative marks might be characterized, allowing for more focused assays in tissue libraries and populations to link variants to regulatory mechanisms. Additionally, it is challenging for a given phenotype to know which cell type(s) are most useful to assay chromatin marks in order to fine map risk alleles. Furthermore if the critical cell types were known, it might be possible to develop cell-specific functional experiments to identify genes impacted by these risk variants. The objectives of this project were: (1) To develop an approach to identify the key pathogenic cell types that are impacted by risk variants and to apply this approach in the context of RA and CD. (2) To identify the most informative chromatin marks, to track the cell specificity of risk variants in order to develop chromatin assays on large tissue/cell type libraries. (3) To identify the regulatory elements impacted by risk variants and by which mechanisms they are affected. (4) To develop an approach to identify the genes impacted by risk variants and to apply this approach in the context of RA and CD. (5) To develop approaches integrating different available genomic data sources to understand the molecular mechanisms of risk variants discovered through genetic studies. The results of this project are: (1) The development of a statistical framework to identify the most informative chromatin mark to track the cell-specificity. (2) The development of an approach to identify critical cell types involved in complex phenotypes. (3) The development of a statistical framework to identify tissue-specific regulatory elements impacted by risk alleles. (4) The development of a statistical framework to identify the genes impacted by disease risk variants. (5) Our approaches have been applied to elucidate the role of risk variants associated with multiple complex diseases, including RA and CD and also Parkinson’s disease and Type 2 diabetes. (6) We published or are publishing our results in peer-reviewed journals. (7) Distribution of the source code of our approaches. (8) Presentation of our results in conferences. (9) Supervision of undergraduate/graduate students and a postdoc on a related research project. Conclusions: We developed approaches to identify regulatory genetic variants involved in complex human diseases, notably RA and CD. The results of this research project will provide a valuable resource to identify: (1) Novel molecular pathways underlying RA and CD or other human complex disease (2) New disease candidates genes, and (3) New target drugs.

Data: CORDIS, © European Union