Scientists map networks that control gene function in the human brain

news release

Friday, May 24, 2024

NIH-funded research details cellular and molecular regulatory elements of the brain and their impact on brain function.

A consortium of researchers has created the largest, most advanced, multidimensional maps of gene regulatory networks in the brains of people with and without psychiatric disorders. These maps detail the many regulatory elements that orchestrate the brain's biological pathways and cellular functions. The study, supported by the National Institutes of Health (NIH), used postmortem brain tissue from more than 2,500 donors to map gene regulatory networks across different stages of brain development and multiple brain-related diseases.

“These groundbreaking discoveries advance our understanding of where, how, and when genetic risk contributes to mental illnesses such as schizophrenia, post-traumatic stress disorder, and depression,” said NIH's National Institute of Mental Health (NIMH) Director Joshua A. Gordon, M.D. “Furthermore, this critical resource, which will be freely shared, will help researchers pinpoint genetic variants that may contribute to psychiatric disorders and identify potential molecular targets for new therapeutics.”

The research has been published in 15 papers in Science, Science Advances and Scientific Reports. The papers report the findings along several key themes:

• Population-level analyses linking genetic variation, regulatory elements, and different molecular forms of expressed genes to cellular-level regulatory networks in both the developing and adult brain
• Single-cell level maps of the prefrontal cortex in individuals diagnosed with psychiatric and neurodevelopmental disorders
• Experimental analyses that test the function of regulatory elements and genetic variants associated with quantitative trait loci (segments of DNA linked to observable traits)

This analysis extends previous findings by examining multiple cortical and subcortical regions of the human brain that play key roles in a variety of important processes, including decision-making, memory, learning, emotion, reward processing, and motor control.

Approximately 2% of the human genome consists of genes that code for proteins. The remaining 98% contains DNA segments that control the activity of these genes. To better understand how brain structure and function influence psychiatric disorders, researchers in the NIMH-funded PsychENCODE Consortium are using standardized methods and data analysis approaches to build a comprehensive picture of these control elements in the human brain.

In addition to these findings, the paper also highlights new methods and tools to help researchers analyze and explore the vast amounts of data generated by this effort. These resources include a web-based platform called PsychSCREEN, which provides interactive visualizations of data from different brain cell types in people with and without psychiatric disorders. Together, these methods and tools provide a comprehensive, integrated data resource for the broader research community.

These papers highlight findings from the second phase of the PsychENCODE consortium, an effort aimed at improving our understanding of how gene regulation influences brain function and dysfunction.

“These findings from the PsychENCODE Consortium shed new light on how genetic risk maps to brain function across developmental stages, brain regions, and diseases,” said Jonathan Pevsner, PhD, director of NIMH's Genomics Research Division. “This study provides a strong foundation for ongoing efforts to characterize regulatory pathways across diseases, elucidate the role of epigenetic mechanisms, and increase the ancestral diversity represented in studies.”

PsychENCODE papers published in Science and Science Advances are publicly available in a collection on the Science website.

About the National Institute of Mental Health (NIMH): NIMH's mission is to transform the understanding and treatment of mental illness through basic and clinical research, paving the way for prevention, recovery, and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH):NIH is the nation's medical research agency, comprised of 27 Institutes and Centers, and is part of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit: Click here for details.

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