Towards finding and understanding the missing heritability of immune-mediated diseases

Immune-mediated diseases, such as Celiac disease, are complex disorders in which environmental and genetic risk factors result in a pro-inflammatory response to otherwise harmless food and body constituents. In Celiac disease the main environmental factors are gluten proteins, present in grain products. Using genetic studies performed in the last decade, more than 300 hundred genomic regions have been identified. Most of these regions contain multiple genes, making it challenging to pinpoint the causal, harmful genes. In this thesis it was aimed to identify novel regions and genes contributing to Celiac disease and to prioritize the causal genes in these and the already known regions To achieve this genetic data from thousands of healthy individuals and patients, as well as gene expression data from blood and tissue samples was combined. By doing so novel regions involved in disease were identified and novel genes and pathways were prioritized. It was discovered that more than one gene in a disease related region can contribute to disease. Moreover, we identified that a recently discovered, novel class of genes is involved in disease pathology (the so-called long non-coding RNAs). Lastly, by analyzing Neanderthal DNA, it was discovered that mating between our ancestors and Neanderthals introduced disease causing factors in the DNA of the modern human. These studies underline the importance of freely available DNA repositories for research. In these studies these were used to better understand the processes that lead to immune-mediated disease in humans.