The Center for Disease Neurogenomics (CDN) is deciphering the origins, mechanisms, and treatments of neuropsychiatric disease. The Center consists of six specialized research groups under the direction of Panos Roussos, MD, PhD, MS, working in concert to understand the complexity of these diseases.
While there has been much progress in genetics, genomic sciences, and precision medicine for cancer and cardiovascular disease, the investigation of the disorders of the brain has not kept pace. The challenge is due in part to the fact that neuropsychiatric disorders are caused by the combination of thousands of genetic variants, each having a small effect on the overall disorder.
We are devising groundbreaking new techniques to meet our objectives. We have developed innovative methods to isolate cells and nuclei to perform cell-type specific assays; new computational and machine learning approaches to generate large-scale functional omics and understand cellular and molecular mechanisms in disease perturbation; and novel predictive models to assess gene expression, disease manifestation, and treatment outcomes. We are functionally validating our findings in cell-type specific contexts. And we are translating these discoveries to uncover new drug targets, repurpose existing drugs for neuropsychiatric diseases, and optimize treatment for each individual based on their genetics.
The Complexity of the Brain Requires a Team Approach
The human brain is a complex and vast field of study, with billions of cells, thousands of cell types, and many different brain regions. In addition, the brain is not a static organ but a dynamic, evolving entity as it ages. Our goal is to map genetic liability across this developmental process, and determine what happens in each brain region, cell type, and the molecular markers in specific time periods as disease progresses.
The complexity of this task requires an interdisciplinary approach. Our research requires the expertise of computational scientists, biomedical scientists, psychiatrists, and genomic scientists. Many of our researchers are cross-trained, with advanced knowledge in six key fields.
The six groups include:
- The Multi-omics Technology Group directed by John Fullard, PhD
- The Multi-omics Data Integration Group directed by Jaroslav Bendl, PhD
- The Computational Neuroepigenomics Group directed by Kiran Girdhar, PhD
- The Statistical Neurogenomics Group directed by Gabriel Hoffman, PhD
- The Single Cell Neurogenomics Group directed by Donghoon Lee, PhD
- The Translational Bioinformatics and Precision Therapeutics Group directed by Georgios Voloudakis, MD, PhD
A World-Wide Leader in Generating Human Brain Omics Data
The Center for Disease Neurogenomics (CDN) has established collaborations to access and utilize thousands of brain tissue samples—both post-mortem and fresh—that allows us to perform brain molecular analysis at population level. The Center is generating multi-omic human brain data at unprecedented depth and breadth—including cell type-specific and single-cell molecular datasets. This multi-layered data allows us to define disease signatures and perturbations and understand the impact of non-coding genetic regions on neuropsychiatric diseases. Mount Sinai’s supercomputer, Minerva, is a powerful resource that enables us to analyze and manage these extraordinary amounts of data.
We belong to, and play leadership roles in, a variety of brain consortia such as PsychENCODE, CommonMind Consortium, Psych-AD, AMP-AD, AMP-PD, and BRAIN Initiative, among others. The scarcity of human brain tissue and the complexity of the questions surrounding neuropsychiatric diseases has fostered a strong community of collaboration and sharing of data. To that end, we develop online data repositories and visualization portals that facilitate an interactive view of multi-omics datasets. We develop public, open-source software using sophisticated statistical methods to analyze large-scale functional genomics datasets, and we distribute software packages to colleagues, collaborators, and the broader genomics field.
Advancing the Power of Precision Medicine
Our goal is to use genetics to be able to predict the severity of the clinical phenotype, optimal treatment, and outcomes for every patient. Ideally, we would not treat every patient with the same medication but be able to determine the most effective treatment with the lower number of side effects based on their genetic profile. However, finding effective drug targets for neuropsychiatric disease is challenging because of the cumulative effect of small genetic risk factors and molecular processes.
To promote Precision Medicine, the CDN utilizes electronic health record data from biobanks, including the Million Veteran Program, the Mount Sinai BioMe database and the UK BioBank. The Million Veteran Program is the world’s largest genomic database linked to a health care system that provides access to the electronic health records and genetic profiles of a vast cohort of patients, many of whom are prone to neuropsychiatric disorders such as post-traumatic stress disorder and depression.
Our research at the genetic, molecular, and cellular level is refining our understanding of drug targets and how they may work in individuals based on their genetic profile. On the immediate horizon, our research is uncovering repurposing indications for existing drugs to treat neuropsychiatric diseases. For instance, we may see that a drug—prescribed for another indication, such as cancer—may be able to correct the genetic profile and disposition for a specific neuropsychiatric disease. Through genetic research we are able to propose models of mechanism, which may advance to preclinical studies, and then early open-label clinical studies.