From left: Kristen Brennand, PhD, Associate Professor, Neuroscience, Genetics and Genomic Sciences, and Psychiatry; Prashanth Rajarajan, MD/PhD candidate; and Schahram Akbarian, MD, PhD, Professor, Psychiatry, and Neuroscience.
Reprinted with permission from AAAS.
More than two dozen researchers at the Icahn School of Medicine at Mount Sinai are advancing brain science by mapping the complex molecular underpinnings of autism spectrum disorder, schizophrenia, and bipolar disorder through their work in the National Institute of Mental Health’s (NIMH) PsychENCODE Consortium. Since this work began in 2015, their contributions—and that of their PsychENCODE colleagues from 14 other U.S. institutions—have helped identify several hundred new risk genes for mental disorders. The research has also revealed critical time windows during brain development when these genes can influence the disease process.
In December, the Consortium published its initial findings in 10 studies that appeared in Science, Science Translational Medicine, and Science Advances. The researchers analyzed more than 2,000 postmortem brain samples from people with no psychiatric conditions and those with schizophrenia, autism, and bipolar disorder. They created and then integrated data sets that included information on DNA variations and gene expression for about 32,000 cells from major regions of the brain. Then the investigators employed machine learning to create a predictive model of risk for the psychiatric disorders.
Their seminal findings received an enthusiastic response from the NIMH. “The PsychENCODE project came through,” said Thomas Lehner, PhD, MPH, Director of the Office of Genomic Research Coordination at the NIMH. “We’re at the beginning—I cannot overstate how early we are. But I can confidently say that for the first time we have a beginning of an understanding of the biology—the molecular pathophysiology of mental disorders—of schizophrenia, and bipolar and autism spectrum disorder.”
Unraveling the Complexity of the Human Brain
“Exploring how the human genome is folded and packaged into the nucleus of each of our billions of brain cells was both awe-inspiring and humbling at the same time,” says Prashanth Rajarajan, MD/PhD candidate at the Icahn School of Medicine at Mount Sinai, who was first author on seminal brain research that was published in the December 14, 2018, issue of Science.
The scientific team discovered that early development is associated with major changes in the spatial organization of DNA inside of brain cells. These changes in how the chromosomal material is packed seem to disproportionately affect DNA sequences linked to schizophrenia heritability risk and provide new insights into the genetic causes underlying this disease.
The study, which was conceived and executed at the Icahn School of Medicine, included senior authors Schahram Akbarian, MD, PhD, Professor, Psychiatry, and Neuroscience; and Kristen Brennand, PhD, Associate Professor, Neuroscience, Genetics and Genomic Sciences, and Psychiatry. Colleagues at the New York Genome Center and the University of Massachusetts also contributed to the study.
According to Mr. Rajarajan, “There is so much more to the genome than just the four-letter DNA code (A, T, C, G)—such as its folded architecture, which is a highly organized and regulated process. Eighteen years after fully sequencing the human genome, we still understand very little about how it actually comes to life. Our study, and the others that were published, are beginning to unravel more nuances than previously imagined, making it a really exciting time to be in the field of neuroscience and psychiatry research.”
NIMH Program Director Geetha Senthil, PhD, added that the massive scope of the project required a “concerted effort. Many investigators had to come together and do this collectively.” While the mental disorders in the studies are distinct, Dr. Senthil said, “There are some aspects where the biology is similar. The genes interact with each other in a way to influence the disease process. If we can find biological clues early on, we can intervene early on. While we are building and generating more data, analyzing this data to find basic mechanisms, there’s an opportunity also for drug discovery.”
The 10 papers published by the PsychENCODE Consortium were dedicated to the late Pamela Sklar, MD, PhD, former Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine, and a pioneer in genomic brain research, who was an early leader of the NIMH effort. The Icahn School of Medicine last year renamed the division she created the Pamela Sklar Division of Psychiatric Genomics.
Mount Sinai laboratories within The Friedman Brain Institute, The Seaver Autism Center for Research and Treatment, the Department of Psychiatry, The Mindich Child Health and Development Institute, the Department of Genetics and Genomic Sciences, the Department of Neuroscience, and the Icahn Institute for Data Science and Genomic Technology were involved in the PsychENCODE Consortium.
“Mount Sinai serves as one of the lead sites in this national consortium. The discoveries that are being made by our scientists and their colleagues at other major institutions are moving us closer to understanding and finding treatments for these devastating brain disorders,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic and Scientific Affairs, Icahn School of Medicine at Mount Sinai.