Scientists create advanced multidimensional maps of gene regulation networks in the brain

A consortium of researchers has created the largest and most advanced multidimensional maps of gene regulatory networks in the brains of people with and without mental disorders. These maps detail many of the regulatory elements that coordinate brain 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 at various stages of brain development and many brain-related disorders.

These breakthrough discoveries advance our understanding of where and how, and when genetic risk contributes to mental disorders such as schizophrenia, post-traumatic stress disorder and depression. Moreover, critical resources, shared freely, will be help researchers pinpoint genetic variants that likely play a causal role in mental illness and identify potential molecular targets for new therapies.”

Joshua A. Gordon, M.D., director of the NIH’s National Institute of Mental Health (NIMH).

The research results were published in 15 articles in Science, Progress of scienceAND Scientific reports. The articles present findings on several key topics:

• Population-level analyzes that link genetic variants, regulatory elements, and different molecular forms of expressed genes to cellular-level regulatory networks in both the developing and adult brain
• Single-cell maps of the prefrontal cortex of people diagnosed with mental and neurodevelopmental disorders
• Experimental analyzes examining the function of regulatory elements and genetic variants associated with quantitative trait loci (DNA segments associated with observable traits)

The analyzes extend previous findings and examine multiple cortical and subcortical areas of the human brain. These brain areas play key roles in a number of fundamental processes, including decision-making, memory, learning, emotion, reward processing, and motor control.

About 2% of the human genome consists of protein-coding genes. The remaining 98% includes DNA segments that help regulate the activity of these genes. To better understand how brain structure and function contribute to mental disorders, scientists in the NIMH-funded PsychENCODE consortium are using standard methods and data analysis approaches to build a comprehensive picture of these regulatory elements in the human brain.

In addition to these discoveries, the articles also highlight new methods and tools that will help researchers analyze and explore the wealth of data generated by these efforts. These resources include an online platform that offers interactive visualization data from different types of brain cells in people with and without mental disorders, known as PsychSCREEN. Together, these methods and tools provide a comprehensive, integrated source of data for the broader research community.

The articles focus on the second phase of the PsychENCODE consortium’s findings. The goal of these efforts is to advance understanding of the impact of gene regulation on brain function and dysfunction.

“The findings of the PsychENCODE consortium shed new light on how gene risk maps to brain function at different stages of development, in different brain areas, and in different disorders,” said Dr. Jonathan Pevsner, chief of NIMH’s Division of Genomic Research. “This work provides a solid foundation for ongoing efforts to characterize the regulatory pathways of various disorders, elucidate the role of epigenetic mechanisms, and increase the ancestral diversity represented in research.”

PsychENCODE articles published in Science AND Progress of science are presented as a collection on the site Science website.