Objective/Rationale:
Complex diseases such as Parkinson’s are caused by a combination of genetic, environmental and lifestyle factors that all lead to different causal regulation mechanisms. Molecular pathways have already been identified that are associated with both genetic and environmental contributions. Causal mechanisms, however, have eluded numerous attempts at fine mapping despite intensive research. We build on the hypothesis that these causal mechanisms can be unraveled and involve genetic and epigenetic disruptions driving these molecular pathways.
Project Description:
We have genotype data as well as RNA sequencing, miRNA, DNA methylation, and histone modification data from the prefrontal cortex of 550 individuals from two prospective cohort studies of aging: the Religious Order Study and the Memory and Aging Project. We will enhance known algorithms to integrate multiple levels of genomic data types to look at the flow of information from DNA to protein. Specifically, we will (1) identify causal genetic and epigenetic mechanisms associated with Parkinson’s disease, (2) identify molecular pathways associated with Parkinson’s disease, and (3) infer combinations of regulatory mechanisms by associating regulators to molecular pathways.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We will develop computational strategies to discover disease mechanisms and therapeutic targets in Parkinson’s disease for better diagnostics and therapy. Identifying the different causal mechanisms at play in different subgroups of individuals will facilitate the design of increasingly specific therapeutic strategies in Parkinson’s disease.
Anticipated Outcome:
More generally, the proposed study will use the power of innovative computational strategies to integrate multiple levels of genomic data towards developing a systematic method for understanding the molecular and mechanistic basis of complex human disease.
Final Outcome
Our integrative genomic approach provides a comprehensive view of the molecular mechanisms underlying Parkinson's disease. We characterized a series of regulatory circuits with repressed mitochondrial function and predictive of a diagnosis of Parkinson's disease and loss of neurons in the substantia nigra. In conjunction, we described a regulatory circuit with genes involved in ubiquitination, a tag for protein degradation, consistent with research that shows that this damage-control apparatus is induced in Parkinson's disease. We showed that genes operating in the peroxisome were repressed in expression, while phospholipids, a component of myelin which aids in neuronal communication, are processed in peroxisomes. In addition, we identified a number of regulatory circuits induced in Parkinson's disease that have a role in GABA biosynthesis and cadherin, a molecule that controls cell adhesion and migration, while other regulatory circuits repressed in Parkinson's disease are enriched for Wnt signaling. In fact, cadherin and Wnt signaling are intertwined in a competitive relationship for the key molecule, β-catenin, which we put under investigation. Lastly, we described a series of regulatory circuits repressed in Parkinson's disease and characterized by neurotrophin and synaptic function, and predict a suite of motor trait dysfunction including gait, rigidity, tremor and bradykinesia. Using this approach, we identified a list of candidate regulators for the perturbation of these networks, which will lend valuable insight into how these regulators affect the cellular circuitries and pave the way for targeted drug design in Parkinson's disease.