Four Studies by Mount Sinai Investigators Featured in Special Issue of Science Focused on Big Data
Publications reflect Mount Sinai Health System’s investment in the exploration of brain genome organization and function
The work of several Mount Sinai researchers who analyze brain genomics data as part of the PsychENCODE Consortium, a collective established in 2015 by the National Institutes of Health (NIH), is highlighted in four scientific papers published online December 13 in the journal Science as part of a special issue focused on big data.
The Icahn School of Medicine at Mount Sinai (ISMMS) is one of the lead sites associated with the PsychENCODE Consortium, a collaboration among NIH grantees that aims to accelerate discovery of non-coding functional genomic elements (components of an organism’s DNA that do not encode protein sequences) and epigenetic modifications (reversible modifications on a cell’s DNA or histones that affect gene expression without altering the DNA sequence) as they relate to gene expression patterns in the human brain and to understand the molecular pathophysiology of mental illness, particularly autism spectrum disorder, bipolar disorder, and schizophrenia.
Having analyzed more than 2,000 normal and disease-affected brains to date, the Consortium is publishing some of its initial findings in the December issue of Science, with multiple collaborative contributions by investigators from ISMMS, including laboratories from The Friedman Brain Institute and the Seaver Autism Center for Research and Treatment.
Below are descriptions of the studies that, with significant contributions by researchers from the Icahn School of Medicine at Mount Sinai, will be published in the journal:
Study Title: Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
Schahram Akbarian, MD, PhD, Professor of Psychiatry and Neuroscience
Kristen Brennand, PhD, Professor of Neuroscience, Genetics and Genomic Sciences, Psychiatry
- Through genome-wide chromosomal mappings in neural precursor cells and differentiating neurons and glial cells, the researchers discovered that early development is associated with major changes in chromosomal conformations inside the nuclei of brain cells. These ‘3D genome’ changes in young neurons disproportionately affect common DNA variants that are associated with schizophrenia heritability, highlighting cell type-specific vulnerabilities in spatial genome organization and expanding the genomic risk space associated with psychiatric disease. For this study, the Mount Sinai investigators joined forces with scientists from the New York Genome Center and the University of Massachusetts Medical School.
Study Title: Comprehensive functional genomic resource and integrative model for the human brain
Schahram Akbarian, MD, PhD, Professor of Psychiatry and Neuroscience
Panos Roussos, MD, PhD, Associate Professor of Genetics and Genomic Sciences, and Psychiatry
- Next-generation sequencing datasets were used to integrate information on gene expression, chromatin structure and function, and genome sequence information to provide an unprecedented resource on genome organization and function in the adult male brain. The dataset is fed into a computer-based deep learning mechanism which will improve disease risk prediction several-fold when compared to conventional genomic approaches.
Study Title: Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
Dalila Pinto, PhD, Assistant Professor of Psychiatry, and Genetics and Genomic Sciences
- By integrating RNA sequencing and genetic data to refine the shared and distinct molecular pathology of autism spectrum disorders, bipolar disorder, and schizophrenia, the multisite research team, co-led by Dr. Pinto and colleagues from the University of California-Los Angeles, the University of California-San Diego, and SUNY Upstate Medical University provided a quantitative, genome-wide resource for mechanistic insight and therapeutic development and an interactive website (http://resource.psychencode.org/) to permit further biological exploration of gene/isoform co-expression networks. These data revealed shared and disorder-specific molecular pathways and cell types involved, emphasized the importance of local splicing and isoform-level gene regulatory mechanisms in defining cell type and disease specificity, and, after further integrating genome-wide association studies, led to the discovery of new candidate risk genes.
Study Title: Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder
Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment and Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences
- Whole genome sequencing (WGS) has facilitated the first large-scale genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, a multisite research team, led by Harvard University, the University of California-San Francisco, Carnegie Mellon University, and the University of Pittsburgh, assessed genetic variation from 7,609 samples in 1,902 autism spectrum disorder (ASD) families, identifying 255,106 de novo mutations—rare, spontaneous mutations that may exert strong effects. In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, is significantly associated with ASD. Casting noncoding variation in the context of a risk score across multiple annotation categories, however, does demonstrate association with mutations localized to promoter regions, regions of DNA that initiate transcription of a particular gene. The strongest driver of this promoter signal emanates from evolutionary conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD risk.
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