Genomics of Complex Diseases

The increasingly comprehensive functional annotation of the human genome provides a unique opportunity to understand diseases of complex genetic origin. Recent advances in genome biology have clearly demonstrated the importance of genetic and epigenetic information in elucidating the pathology of diseases such as type 2 diabetes and psychiatric diseases. However, our understanding of the molecular origin and progression of these diseases remains limited and poses one of the most pressing challenges of modern biomedical research. These diseases are not caused by a single factor, but are rather determined by the complex interplay of many genetic and environmental contributions.

General difficulties arise due to an etiology that is characterized by polygenicity and a complex interplay of multiple genetic, epigenetic and environmental factors. This problem has been particularly prevalent with respect to psychiatric diseases and little is known about their molecular determinants. Hence, our research is focused on the question how many genetic and environmental risk factors act in concert to create a permissive molecular environment that fosters the emergence of psychiatric disorders such as Schizophrenia.

To address these challenges, the lab for Genomics of Complex Diseases (PI: Dr. Ziller) develops and applies functional systems genomics approaches in order to dissect the genetic and epigenetic architecture of complex (disease) phenotypes using in vitro differentiation models of human pluripotent cells with a particular focus on schizophrenia.

Schizophrenia (SCZ) is one of the most devastating diseases of the nervous system, affecting approximately 1% of the population. Despite the enormous disease burden, little is known about the exact molecular mechanisms leading to disease onset and progression. Genetics offer a compelling handle on the biology of SCZ due to its high heritability (~80%) and genome wide association studies have identified thousands of genetic variants to be associated with SCZ. However, the capacity to translate these associations to insights on disease mechanisms has been challenging in SCZ like in most other genetically complex diseases due to their likely polygenic architecture and the fact that most variants exhibit only very small effect sizes.

The Ziller lab is committed to address these challenges and dissect the genetic basis of SCZ in order to translate genetic associations into an understanding of the molecular disease mechanisms.

To implement this goal, we pursue the hypothesis that SCZ pathology is driven by the interplay of many common and rare genetic variants that act in concert in neural cell populations.

To test this hypothesis, we employ a highly interdisciplinary approach, that utilizes pluripotent stem cell based neural differentiation paradigms (Ziller et al. Nature 2014, Gifford* & Ziller* et al. Cell 2013), SCZ patient specific iPSCs, functional (epi-)-genomic approaches (ChIP-Seq, high-throughput genetic screens) (Cacchiarelli*, Trapnell* & Ziller* et al. Cell 2015, Galonska* & Ziller* et al., Cell Stem Cell, 2015, Ziller et al., Nature 2013, Ziller et al., PLoS Genetics 2011) and computational modeling strategies (Ziller et al. Nature 2014).

This research agenda will allow to deconvolute how the combination of many genetic and epigenetic alterations can lead to onset and progression of psychiatric diseases such as schizophrenia by identifying molecular and macroscopic phentoypes in disease relevant cell populations.



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