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PsychENCODE Research Collection Uncovers Molecular Processes in Brain Development, Disease

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NEW YORK – Members of the PsychENCODE2 Consortium have shared findings from a broad swath of molecular analyses aimed at understanding brain development, brain function, and related neuropsychiatric or neurodegenerative conditions, providing new insights into the biological processes behind neurodevelopmental conditions or mental illness.

The PsychENCODE Consortium, which began nearly a decade ago, represents an effort aimed at untangling features found in conditions such as autism spectrum disorder (ASD), schizophrenia, or bipolar disorder, the authors explained. The group's results appeared in a collection of papers in Science, Science Translational Medicine, and Science Advances on Thursday.

"The current PsychENCODE2 collection builds on previous work by providing a resource for identifying genomic regions that regulate gene expression in the brain across various developmental and adult stages," Gaia Novarino, with the Institute of Science and Technology Austria, and Christoph Bock, with the Austrian Academy of Sciences and the Medical University of Vienna, wrote in a related perspectives article in Science.

In a study appearing in Science, investigators from the University of California, Los Angeles, the University of Pennsylvania, and elsewhere reported outlined efforts to understand transcript splicing and isoform diversity found in neocortex samples from developing human brains, along with cell type-specific expression of certain transcripts.

"We knew, based on our previous research, that isoform regulation is a key molecular feature for understanding brain development and genetic risk for neuropsychiatric disorders," co-senior and co-corresponding author Luis de la Torre-Ubieta at UCLA said in a statement.

With the help of deep long-read Pacific Biosciences HiFi Iso-Seq sequencing, the team assessed neocortex germinal zone and cortical plate region samples from half a dozen mid-gestation fetal donors, documenting differential transcript expression and usage at the tissue level during neurogenesis. The analyses uncovered more than 214,500 new and known transcript isoforms, while highlighting brain development-related isoform changes with potential relevance for understanding brain-related conditions.

"We found that high-confidence risk genes for autism or neurodevelopmental disorders tend to be genes that have more isoforms, and those isoforms are expressed differently during neurogenesis," de la Torre-Ubieta explained. "This implies that dysregulation of the expression of specific isoforms is a potential mechanism underlying these disorders."

For a PsychENCODE effort dubbed BrainSCOPE, meanwhile, a team from Yale University, UCLA, the University of Wisconsin-Madison, and elsewhere used single-nucleus RNA-seq (snRNA-seq), single-nucleus ATAC-seq, and single-nuclei multiome approaches to profile gene expression and related gene regulatory patterns in prefrontal cortex samples from 388 individuals, including representatives with neurodegenerative disorders, neuropsychiatric conditions, and neurologically healthy control individuals.

"Overall, the BrainSCOPE resource has the potential to facilitate precision medicine by linking variants to specific cell types and their cell type-specific impacts — for example, to help identify the cell type of action for potential therapies," the authors explained.

In another single-cell sequencing study, also appearing in Science, researchers at MIT, Harvard Medical School, Icahn School of Medicine at Mount Sinai, and other centers turned to snNA-seq to track transcript expression in postmortem prefrontal cortex samples from 65 individuals with schizophrenia and 75 unaffected controls.

Based on transcriptome data for 468,727 individual cells, they flagged pathways and cell types marked by the most pronounced schizophrenia-related shifts and distinguished between schizophrenia cases with gene expression changes linked to the cell states found in either excitatory or inhibitory neurons.

"The data presented here complement those from others in the field and offer a cell type-specific reframing of schizophrenia transcriptional pathology by revealing specific cell populations affected by schizophrenia genes, variants, and regulators," co-senior authors Manolis Kellis, with the Broad Institute and the Massachusetts Institute of Technology, and Panos Roussos, with the Icahn School of Medicine at Mount Sinai and Milan's Neurogenomics Research Center, and their colleagues wrote.

UCLA's Brie Wamsley led a team that took a closer look at ASD contributors, using deep single-nucleus RNA-seq on postmortem frontal cortex samples from 33 ASD cases and 30 control individuals — an effort that revealed ASD-associated gene regulatory changes that were subsequently validated with additional spatial transcriptomic and single-nucleus ATAC-seq analyses.

"The depth and breadth of this single-cell analysis, involving large numbers of individuals and cells profiled, solidifies the picture of the major cortical cell types affected in ASD, including alterations in cell type composition, remodeling of cell states, and the identification of cell type-specific transcriptional cascades," the authors reported in Science.

Still other studies, published in Science Advances and Science Translational Medicine focused on cell types, regulatory elements, and sex-specific transcriptional features related to neurodegenerative or neuropsychiatric diseases, among other things.

In their perspectives article, Novarino and Bock noted that the new collection of PsychENCODE studies "mark a substantial step forward for neurogenetics by providing an overview of gene regulatory regions and associated gene expression patterns in the human brain."