Neuropsychiatric Disease Genomics

One of the signature projects of the NPD genomics program is the Genomic Medicine for Mental Health Advancement (GeMMA) initiative, which aims to develop a patient-centric platform for precision psychiatry. GeMMA, a collaboration between the NYGC, Columbia University, Northwell Health, and the New York State Office of Mental Health (NYS OMH), will be dedicated to providing patients with access to evidence-based mental health care and the integration of genetic and clinical records into prognosis, diagnosis, and clinical care. The platform’s initial target population are the historically underserved patients of the New York State mental health system.

The group is also leading efforts to ensure our ability to share genomic data responsibly without compromising data security or patient privacy. In psychiatric research, safeguarding patient privacy and securing genotypic and phenotypic data is of paramount importance, given the highly sensitive nature of mental health information and the stigma frequently associated with psychiatric diagnoses. Dr. Gamze Gursoy’s lab at the NYGC is working to create a privacy-enhancing, cloud-ready, user-friendly, and modular genotype-phenotype ecosystem of tools that not only aid current research efforts but also ensure solutions are finely tuned to meet the unique needs of this vulnerable patient population.

The group is building off the large dataset produced by the NYGC as part of the Centers for Common Disease Genomics, funded by the NHGRI. As part of this effort, the NYGC generated whole genome sequencing data on over 37,000 individuals from families with at least one member affected by autism spectrum disorder. In an ongoing project, Dr. Tarjinder Singh and Dr. Thomas Lehner are exploring the genetic and phenotypic architecture of schizophrenia with a focus on whole genome sequencing of severe cases from the Genomic Psychiatry Cohort (GPC), in collaboration with Drs. Carlos and Michelle Pato at Rutgers University. The GPC is a large, diverse, and deeply phenotyped cohort of individuals with clinician-verified psychiatric diagnoses and screened controls, which represents a unique opportunity for genomic analyses using factors such as age of onset, treatment resistance, and long-term hospitalization to maximize our chance of discovering novel variants and realizing clinical utility.

Drs. Singh and Lehner, along with Dr. Michael Zody, are also part of the recently launched Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2) Genetics Platform. This project, led by collaborators at the Broad Institute and UCLA, aims to sequence one of the largest and most diverse cohorts of people with bipolar disorder.

The NYGC is leading an effort to delineate causal mechanisms of bipolar disorder using scalable functional patient-derived neuron models as part of the BD2 Discovery Platform. This project, a collaboration with Dr. Carlos Pato and Dr. Michele Pato at Rutgers University, will leverage the Genomic Psychiatry Cohort (GPC), which encompasses a large, diverse cohort of individuals with mental disorders and neurotypical controls. The team, which includes Drs. Thomas Lehner, Tarjinder Singh, Neville Sanjana, and Tuuli Lappalainen, will perform multimodal analyses of neuronal stem cells derived from blood samples donated by GPC participants of African descent to investigate the biological consequences of common genetic variants by comparing those with high genetic risk to those with low risk, and using massively-parallel CRISPR-based genomic approaches. The team will also use genetic engineering to study the biological consequences of rare mutations known to have large effects on the population.

A growing body of evidence is also pointing to a critical role for higher-order chromatin organization in neurodevelopment. This organization encompasses the compartmentalization of chromatin into specific regions such as topologically associated domains, loops, and frequently interacting regions, all of which modulate the interactions between regulatory elements such as enhancers and gene promoters. Dr. Gamze Gursoy and her team are developing tools to map these interactions in order to investigate the contributions of regulatory variation in the non-coding genome to the molecular phenotypes associated with neurodevelopmental disorders, such as ASD.